Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target for a Therapeutic Approach

*Stavros J. Baloyannis*

## **Abstract**

Alzheimer's disease remains the main cause of dementia in advanced age worldwide. Among the etiopathological background of the disease mitochondrial alterations may play a crucial role, given that they are closely related to metabolic and energy deficiency in neurons, glia, and endothelial cells in Alzheimer's disease and other neurodegenerative disorders. In a series of morphological and morphometric studies of mitochondria in the cerebrum and the cerebellar cortex in Alzheimer's disease, by electron microscopy, we described marked morphological and morphometric alterations. The most frequent ultrastructural alterations of the mitochondria consist of disruption of the cristae, accumulation of osmiophilic material, and marked changes of shape and size in comparison with the normal controls. Mitochondrial alterations were particularly prominent in dendritic profiles and dendritic spines. The ultrastructural study of a substantial number of neurons in the cerebellum revealed that mitochondrial alterations do not coexist, as a rule, with the typical Alzheimer's pathology, such as cytoskeletal alterations, amyloid deposits, and tau pathology, though they are frequently observed coexisting with alterations of the cisternae of the Golgi apparatus. Therapeutical regimes targeting mitochondria may be beneficial in early cases of Alzheimer's disease.

**Keywords:** Alzheimer's disease, Mitochondria, Electron microscopy, Oxidative stress Treatment, cerebrum, cerebellum

### **1. Introduction**

Alzheimer's disease is the main causative factor of presenile and senile dementia [1] involving a large number of potential pathogenetic mechanisms, which for years was extinguishing the mental capacities, affecting seriously the cognition of the patients and leading to a tragic epilogue of the life with many social, economic and humanitarian consequences.

The phenomenology of familial or sporadic Alzheimer's disease is the final act of a drama, which gradually was causing selective and progressive neuronal loss [2], extensive synaptic alterations [3, 4], progressive neurofibrillary degeneration [5] resulting in intracellular accumulation of hyperphosphorylated tau protein [6], in the form of neurofibrillary tangles, with a parallel accumulation of extracellular

deposits of Aβ peptide forming neuritic plaques with an obvious microglial involvement [7]. The accumulation of the Aβ peptide as the main causative factor in Alzheimer's disease has been the core of the amyloid cascade hypothesis, which gained a considerable reputation, attempting to interpret all the pathological phenomena in the stream of the morphological and functional disintegration in Alzheimer's disease [8].

However, a substantial body of evidence underlines the increasing differentiation from the amyloid hypothesis [9] and emphasizes the crucial role that mitochondrial alterations and dysfunction may play in the pathogenesis of Alzheimer's disease and other neurodegenerative disorders [10–14].

Mitochondria are double membraned organelles, which are the cardinal energy suppliers of the eukaryotic cells by generating ATP, via oxidative phosphorylation. Mitochondria have their circular, double-stranded DNA (mtDNA), encoding thirteen proteins essential for oxidative phosphorylation [15], which is continuously processed by five protein complexes of the respiratory chain (complexes I-V).

Mitochondrial DNA plays reasonably a crucial role in the homeostatic mechanisms of the cell, by providing the essential energetic background for most of the cellular procedures. Moreover, mitochondrial DNA is also involved in a significant number of functional pathways, concerning cellular signaling by generating reactive oxygen species (ROS) synthesis of neurotransmitters at the presynaptic terminals. It is reasonable, that based on their multidimensional activity, mitochondria would be versatile structures, continuously renewed by fusion and fission [16] and frail to degradation thru mitophagy [17, 18].

Mitochondrial morphology is mainly modulated by the neurofilaments and microtubules, given that mitochondria are mostly transported along the microtubules [19], expressing at the same time an immediate adaptation to energetic needs and immune responses of the cells [20]. The fact that mitochondria have an antiviral signaling protein (MAVS), in connection to the outer membrane, emphasizes their importance in activating immune reactions [21] and participating in antiviral responses [22].

In Alzheimer's disease, the mitochondrial alterations, are responsible for the reduced energy production, oxidative stress, and the inflammatory reactions [23], which are among the early phenomena of the disease [24, 25], in the broad spectrum of the functional and morphological alterations [26, 27], which occur affecting progressively the neuronal and synaptic integrity.

Mitochondrial alterations resulting in substantial oxidative stress have been described in a considerable number of neurodegenerative diseases [28–30], a fact which emphasizes the importance of mitochondria morphological and functional integrity in the normal life and long survival of neurons and glial cells. Oxidative stress triggers also the initiation of a real cascade of pathological phenomena, including the modulation of innate immunity, which provokes a further mitochondrial dysfunction, given that mitochondria and mtDNA are very sensitive to oxidative stress [31, 32]. Besides, the association of oxidative stress with the increased accumulation of calcium ions [33], would also be considered among the principal causes of apoptosis [34].

Oxidative stress in Alzheimer's disease is mostly related to amyloid β (Αβ) accumulation in the neocortex [35, 36], which is a phenomenon playing a crucial role in the pathogenetic process of Alzheimer's disease [37]. The mitochondrial dysfunction has culminated with the existent beta-Amyloid toxicity in connection with the decreased rate of glycolysis [38] and the inhibition of the mitochondrial cytochrome c oxidase by a dimeric conformer of Aβ42 [39, 40]. Besides, the increasingly synthesized reactive oxygen species (ROS), aggravate the mitochondrial dysfunction, increase the mitochondrial Ca load [41], initiating mitophagy eventually [42].

**93**

[44, 45].

*Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target…*

the mitochondrial function and exacerbate oxidative stress [49].

nal oxidative stress [41], initiating mitophagy eventually [42].

the mitochondrial activity and exacerbate oxidative stress [49].

However, mitochondrial ROS in low levels may play a positive role acting as second messengers and controlling several physiological processes [43]. Also, ROS are considered as being responsible for NLRP3 inflammasome activation [44, 45]. In excessive ROS synthesis the endogenous antioxidant defense system, such as superoxide dismutase, glutathione peroxidase, superoxide reductase, catalase, are unable to counteract the ROS's vulnerability. It is also significant, that cytosolic mtDNA may activate the NLRP3 inflammasome increasing, even more, the inflam-

Also, the hyperphosphorylated tau protein interacts with the voltage-dependent anion channel 1 (VDAC1) protein, affecting mitochondrial pores and deteriorating mitochondrial activity [47]. In a parallel way, caspase-cleaved tau impairs mitochondrial dynamics in Alzheimer's disease [48]. Therefore, it seems that the convergence of amyloid and tau pathology on mitochondria impair synergistically

From the morphological point of view, the shape and the size of mitochondria are highly variable depending upon the fusion and fission processes, which are regulated by mitofusins (Mfn-1 and Mfn- 2) and optic atrophy protein- 1 (OPA- 1) [50]. From the morphometric point of view, the number of the mitochondria varies in the soma and neuronal processes, according to the energy state of the cell, given that they are transported and accumulated to regions where energy demands and

In Alzheimer's disease, morphological alterations of the mitochondria have been

Mitochondrial trafficking in Alzheimer's disease plays also an important role in abnormal mitochondrial positioning and accumulation. Mitochondrial motility is controlled normally by kinesin and dynein which are powered by ATP hydrolysis, whereas the immobilization of mitochondria in places of high energy consumption is controlled by syntaphilin [56]. In Alzheimer's disease, the hyperphosphorylated tau protein at AT8 sites (ROS), as by-products of the respiration chain, aggravates the mitochondrial dysfunction, increases the mitochondrial Ca load and the neuro-

However, mitochondrial ROS in low levels may play a positive role acting as second messengers and controlling several physiological processes [43]. I addition, ROS are considered as being responsible for NLRP3 inflammasome activation

On the contrary, in excessive ROS synthesis the endogenous antioxidant defense system, is unable to counteract the ROS's vulnerability. It is also significant the fact, that cytosolic mtDNA may activate the NLRP3 inflammasome increasing, even

Besides the hyperphosphorylated tau protein interacts with the voltage-dependent anion channel 1 (VDAC1) protein, affecting mitochondrial pores and deteriorating mitochondrial function [47]. In a parallel way, caspase-cleaved tau impairs mitochondrial dynamics in Alzheimer's disease [48]. Therefore, it seems that the convergence of amyloid and tau pathology on mitochondria impair synergistically

From the morphological point of view, the shape and the size of mitochondria are highly variable depending upon the fusion and fission processes, which are regulated by mitofusins (Mfn-1 and Mfn-2) and optic atrophy protein-1 (OPA-1). [50]. From the morphometric point of view, the number of the mitochondria varies

described [11, 52, 53] even in the early cases of the disease [11] coinciding with dendritic and synaptic pathology [54]. Some evidence suggests that the interaction of mitochondrial fission protein DRP- 1 with the Aβ peptide and the hyperphosphorylated tau protein results in mitochondrial fragmentation increasing therefore

*DOI: http://dx.doi.org/10.5772/intechopen.98436*

ATP consumption are particularly high [51].

the mitochondrial damage [55].

more, the inflammatory reactions [46].

matory reactions [46].

*Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target… DOI: http://dx.doi.org/10.5772/intechopen.98436*

However, mitochondrial ROS in low levels may play a positive role acting as second messengers and controlling several physiological processes [43]. Also, ROS are considered as being responsible for NLRP3 inflammasome activation [44, 45].

In excessive ROS synthesis the endogenous antioxidant defense system, such as superoxide dismutase, glutathione peroxidase, superoxide reductase, catalase, are unable to counteract the ROS's vulnerability. It is also significant, that cytosolic mtDNA may activate the NLRP3 inflammasome increasing, even more, the inflammatory reactions [46].

Also, the hyperphosphorylated tau protein interacts with the voltage-dependent anion channel 1 (VDAC1) protein, affecting mitochondrial pores and deteriorating mitochondrial activity [47]. In a parallel way, caspase-cleaved tau impairs mitochondrial dynamics in Alzheimer's disease [48]. Therefore, it seems that the convergence of amyloid and tau pathology on mitochondria impair synergistically the mitochondrial function and exacerbate oxidative stress [49].

From the morphological point of view, the shape and the size of mitochondria are highly variable depending upon the fusion and fission processes, which are regulated by mitofusins (Mfn-1 and Mfn- 2) and optic atrophy protein- 1 (OPA- 1) [50]. From the morphometric point of view, the number of the mitochondria varies in the soma and neuronal processes, according to the energy state of the cell, given that they are transported and accumulated to regions where energy demands and ATP consumption are particularly high [51].

In Alzheimer's disease, morphological alterations of the mitochondria have been described [11, 52, 53] even in the early cases of the disease [11] coinciding with dendritic and synaptic pathology [54]. Some evidence suggests that the interaction of mitochondrial fission protein DRP- 1 with the Aβ peptide and the hyperphosphorylated tau protein results in mitochondrial fragmentation increasing therefore the mitochondrial damage [55].

Mitochondrial trafficking in Alzheimer's disease plays also an important role in abnormal mitochondrial positioning and accumulation. Mitochondrial motility is controlled normally by kinesin and dynein which are powered by ATP hydrolysis, whereas the immobilization of mitochondria in places of high energy consumption is controlled by syntaphilin [56]. In Alzheimer's disease, the hyperphosphorylated tau protein at AT8 sites (ROS), as by-products of the respiration chain, aggravates the mitochondrial dysfunction, increases the mitochondrial Ca load and the neuronal oxidative stress [41], initiating mitophagy eventually [42].

However, mitochondrial ROS in low levels may play a positive role acting as second messengers and controlling several physiological processes [43]. I addition, ROS are considered as being responsible for NLRP3 inflammasome activation [44, 45].

On the contrary, in excessive ROS synthesis the endogenous antioxidant defense system, is unable to counteract the ROS's vulnerability. It is also significant the fact, that cytosolic mtDNA may activate the NLRP3 inflammasome increasing, even more, the inflammatory reactions [46].

Besides the hyperphosphorylated tau protein interacts with the voltage-dependent anion channel 1 (VDAC1) protein, affecting mitochondrial pores and deteriorating mitochondrial function [47]. In a parallel way, caspase-cleaved tau impairs mitochondrial dynamics in Alzheimer's disease [48]. Therefore, it seems that the convergence of amyloid and tau pathology on mitochondria impair synergistically the mitochondrial activity and exacerbate oxidative stress [49].

From the morphological point of view, the shape and the size of mitochondria are highly variable depending upon the fusion and fission processes, which are regulated by mitofusins (Mfn-1 and Mfn-2) and optic atrophy protein-1 (OPA-1). [50]. From the morphometric point of view, the number of the mitochondria varies

*Cerebral and Cerebellar Cortex – Interaction and Dynamics in Health and Disease*

disease and other neurodegenerative disorders [10–14].

and frail to degradation thru mitophagy [17, 18].

ing progressively the neuronal and synaptic integrity.

Alzheimer's disease [8].

responses [22].

causes of apoptosis [34].

deposits of Aβ peptide forming neuritic plaques with an obvious microglial involvement [7]. The accumulation of the Aβ peptide as the main causative factor in Alzheimer's disease has been the core of the amyloid cascade hypothesis, which gained a considerable reputation, attempting to interpret all the pathological phenomena in the stream of the morphological and functional disintegration in

However, a substantial body of evidence underlines the increasing differentiation from the amyloid hypothesis [9] and emphasizes the crucial role that mitochondrial alterations and dysfunction may play in the pathogenesis of Alzheimer's

Mitochondria are double membraned organelles, which are the cardinal energy

suppliers of the eukaryotic cells by generating ATP, via oxidative phosphorylation. Mitochondria have their circular, double-stranded DNA (mtDNA), encoding thirteen proteins essential for oxidative phosphorylation [15], which is continuously processed by five protein complexes of the respiratory chain (complexes I-V). Mitochondrial DNA plays reasonably a crucial role in the homeostatic mechanisms of the cell, by providing the essential energetic background for most of the cellular procedures. Moreover, mitochondrial DNA is also involved in a significant number of functional pathways, concerning cellular signaling by generating reactive oxygen species (ROS) synthesis of neurotransmitters at the presynaptic terminals. It is reasonable, that based on their multidimensional activity, mitochondria would be versatile structures, continuously renewed by fusion and fission [16]

Mitochondrial morphology is mainly modulated by the neurofilaments and microtubules, given that mitochondria are mostly transported along the microtubules [19], expressing at the same time an immediate adaptation to energetic needs and immune responses of the cells [20]. The fact that mitochondria have an antiviral signaling protein (MAVS), in connection to the outer membrane, emphasizes their importance in activating immune reactions [21] and participating in antiviral

In Alzheimer's disease, the mitochondrial alterations, are responsible for the reduced energy production, oxidative stress, and the inflammatory reactions [23], which are among the early phenomena of the disease [24, 25], in the broad spectrum of the functional and morphological alterations [26, 27], which occur affect-

Mitochondrial alterations resulting in substantial oxidative stress have been described in a considerable number of neurodegenerative diseases [28–30], a fact which emphasizes the importance of mitochondria morphological and functional integrity in the normal life and long survival of neurons and glial cells. Oxidative stress triggers also the initiation of a real cascade of pathological phenomena, including the modulation of innate immunity, which provokes a further mitochondrial dysfunction, given that mitochondria and mtDNA are very sensitive to oxidative stress [31, 32]. Besides, the association of oxidative stress with the increased accumulation of calcium ions [33], would also be considered among the principal

Oxidative stress in Alzheimer's disease is mostly related to amyloid β (Αβ) accumulation in the neocortex [35, 36], which is a phenomenon playing a crucial role in the pathogenetic process of Alzheimer's disease [37]. The mitochondrial dysfunction has culminated with the existent beta-Amyloid toxicity in connection with the decreased rate of glycolysis [38] and the inhibition of the mitochondrial cytochrome c oxidase by a dimeric conformer of Aβ42 [39, 40]. Besides, the increasingly synthesized reactive oxygen species (ROS), aggravate the mitochondrial dysfunction, increase the mitochondrial Ca load [41], initiating mitophagy eventually [42].

**92**

in the soma and neuronal processes, according to the energy state of the cell, given that they are transported and accumulated to regions where energy demands and ATP consumption are particularly high [51].

In Alzheimer's disease, morphological alterations of the mitochondria have been described [11, 52, 53] even in the early case of the disease [11] coinciding with dendritic and synaptic pathology [54]. Some evidence suggests that the interaction of mitochondrial fission protein DRP- 1 with the Aβ peptide and the hyperphosphorylated tau protein results in mitochondrial fragmentation increasing therefore the mitochondrial damage [55].

Mitochondrial trafficking in Alzheimer's disease plays also an important role in abnormal mitochondrial positioning and accumulation. Mitochondrial motility is controlled normally by kinesin and dynein which are powered by ATP hydrolysis, whereas the immobilization of mitochondria in places of high energy consumption is controlled by syntaphilin [56].

In Alzheimer's disease, the hyperphosphorylated tau protein at AT8 sites [57] may impede the mitochondrial transport via microtubules, leading to improper distribution of mitochondria in giant spines and abnormal synapses [58, 59]. In parallel, oligomers of Ab peptide impair mostly the anterograde movement of mitochondria [60], increasing the number of stationary mitochondria in the neuronal soma.

The observation that mitochondrial abnormalities occur as an early phenomenon in Alzheimer's disease [11], supports the hypothesis that mitochondrial degeneration plays a primal role in Alzheimer's disease pathogenetic procedure, inducing a chain of pathological alterations involving tau and amyloid pathology. Morphological alteration of mitochondria, as well as abnormal interconnections of mitochondria with neurofilaments and microtubules, have been described at the level of electron microscopy in dendrites, axons, and synaptic components, a fact which emphasizes the close association of mitochondrial pathology with the broad pattern of the morphological changes in Alzheimer's disease [61, 62].

In this study, which is an extensive observation on electron microscopy, we attempted to describe the morphological alterations of mitochondria in early cases of Alzheimer's disease in neurons from various areas of the cerebral and cerebellar cortex, proposing also therapeutic approaches in the initial stages of Alzheimer's disease, based on the existing mitochondrial pathology.

#### **2. Material and methods**

#### **2.1 Material**

For describing the morphological alterations of neuron's organelles in early cases of Alzheimer's disease by electron microscopy we focused our observation mostly on the mitochondria in twenty-two cases, fourteen men and eight women, aged 52–87 years, who fulfilled all the clinical, neuropsychological [63] and laboratory diagnostic criteria of Alzheimer's disease.

The brains were derived from patients, who died accidentally 24 to 46 months following the clinical diagnosis of Alzheimer's disease. Additional 15 brains, macroscopically intact derived from apparently healthy persons of parallel age with the patients, were used as normal controls.

Multiple samples from many areas of the brain, namely from the prefrontal area of the frontal lobe, the frontal pole, the acoustic cortex, the visual cortex, the parietal lobe, the insula, the vermis of the cerebellum, and the cerebellar hemispheres were taken in a room temperature of 40 C., 4 to 5 hours after death. Samples

**95**

**Figure 1.**

*(Mag. 72,000 X).*

*Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target…*

also from the hippocampus, the hypothalamus, the mammillary bodies, the locus coeruleus, the red nucleus, the globus pallidus were excised under the same conditions, processed for electron microscopy, and the findings were described and in

All the specimens were immediately immersed in Sotelo [64] fixing solution, for three hours, then post-fixed in osmium tetroxide for 30 min. and dehydrated in graded alcohol solutions and propylene oxide. Thin sections were cut in a Reichert ultratome, contrasted, with uranyl acetate and lead citrate, and studied in electron microscopes Elmiscope 1 and Zeiss 9As. All the methodological and technical details of the preparation of the specimens for electron microscopy have been described

Following the morphological description of the mitochondria, we proceeded also to morphometric estimations on micrographs of a standard magnification of

The methodology of the morphometric estimation of the mitochondria and the statistical analysis of the data have been extensively described in our previous

The mitochondria in cases of Alzheimer's disease demonstrate a wide variation of size and shape in comparison with the mitochondria of normal control brains (**Figure 1**). We noticed that numerous mitochondria were small round or elongated, particularly those which were inside the dendritic profiles or the synaptic terminals

*Mitochondrion of a Purkinje cell of the cerebellum of 75 years old man unremarkable neurologically.* 

*DOI: http://dx.doi.org/10.5772/intechopen.98436*

extensively in our previous reports [65, 66].

previous reports.

**2.2 Method**

56.000X.

reports [11, 65].

**3. Results**

(**Figure 2**).

*Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target… DOI: http://dx.doi.org/10.5772/intechopen.98436*

also from the hippocampus, the hypothalamus, the mammillary bodies, the locus coeruleus, the red nucleus, the globus pallidus were excised under the same conditions, processed for electron microscopy, and the findings were described and in previous reports.

#### **2.2 Method**

*Cerebral and Cerebellar Cortex – Interaction and Dynamics in Health and Disease*

ATP consumption are particularly high [51].

the mitochondrial damage [55].

is controlled by syntaphilin [56].

**2. Material and methods**

diagnostic criteria of Alzheimer's disease.

patients, were used as normal controls.

spheres were taken in a room temperature of 40

**2.1 Material**

neuronal soma.

in the soma and neuronal processes, according to the energy state of the cell, given that they are transported and accumulated to regions where energy demands and

In Alzheimer's disease, morphological alterations of the mitochondria have been described [11, 52, 53] even in the early case of the disease [11] coinciding with dendritic and synaptic pathology [54]. Some evidence suggests that the interaction of mitochondrial fission protein DRP- 1 with the Aβ peptide and the hyperphosphorylated tau protein results in mitochondrial fragmentation increasing therefore

Mitochondrial trafficking in Alzheimer's disease plays also an important role in abnormal mitochondrial positioning and accumulation. Mitochondrial motility is controlled normally by kinesin and dynein which are powered by ATP hydrolysis, whereas the immobilization of mitochondria in places of high energy consumption

In Alzheimer's disease, the hyperphosphorylated tau protein at AT8 sites [57] may impede the mitochondrial transport via microtubules, leading to improper distribution of mitochondria in giant spines and abnormal synapses [58, 59]. In parallel, oligomers of Ab peptide impair mostly the anterograde movement of mitochondria [60], increasing the number of stationary mitochondria in the

The observation that mitochondrial abnormalities occur as an early phenomenon in Alzheimer's disease [11], supports the hypothesis that mitochondrial degeneration plays a primal role in Alzheimer's disease pathogenetic procedure, inducing a chain of pathological alterations involving tau and amyloid pathology. Morphological alteration of mitochondria, as well as abnormal interconnections of mitochondria with neurofilaments and microtubules, have been described at the level of electron microscopy in dendrites, axons, and synaptic components, a fact which emphasizes the close association of mitochondrial pathology with the broad

In this study, which is an extensive observation on electron microscopy, we attempted to describe the morphological alterations of mitochondria in early cases of Alzheimer's disease in neurons from various areas of the cerebral and cerebellar cortex, proposing also therapeutic approaches in the initial stages of Alzheimer's

For describing the morphological alterations of neuron's organelles in early cases of Alzheimer's disease by electron microscopy we focused our observation mostly on the mitochondria in twenty-two cases, fourteen men and eight women, aged 52–87 years, who fulfilled all the clinical, neuropsychological [63] and laboratory

The brains were derived from patients, who died accidentally 24 to 46 months following the clinical diagnosis of Alzheimer's disease. Additional 15 brains, macroscopically intact derived from apparently healthy persons of parallel age with the

Multiple samples from many areas of the brain, namely from the prefrontal area of the frontal lobe, the frontal pole, the acoustic cortex, the visual cortex, the parietal lobe, the insula, the vermis of the cerebellum, and the cerebellar hemi-

C., 4 to 5 hours after death. Samples

pattern of the morphological changes in Alzheimer's disease [61, 62].

disease, based on the existing mitochondrial pathology.

**94**

All the specimens were immediately immersed in Sotelo [64] fixing solution, for three hours, then post-fixed in osmium tetroxide for 30 min. and dehydrated in graded alcohol solutions and propylene oxide. Thin sections were cut in a Reichert ultratome, contrasted, with uranyl acetate and lead citrate, and studied in electron microscopes Elmiscope 1 and Zeiss 9As. All the methodological and technical details of the preparation of the specimens for electron microscopy have been described extensively in our previous reports [65, 66].

Following the morphological description of the mitochondria, we proceeded also to morphometric estimations on micrographs of a standard magnification of 56.000X.

The methodology of the morphometric estimation of the mitochondria and the statistical analysis of the data have been extensively described in our previous reports [11, 65].

#### **3. Results**

The mitochondria in cases of Alzheimer's disease demonstrate a wide variation of size and shape in comparison with the mitochondria of normal control brains (**Figure 1**). We noticed that numerous mitochondria were small round or elongated, particularly those which were inside the dendritic profiles or the synaptic terminals (**Figure 2**).

#### **Figure 1.**

*Mitochondrion of a Purkinje cell of the cerebellum of 75 years old man unremarkable neurologically. (Mag. 72,000 X).*

#### **Figure 2.**

*Mitochondrial alterations in synaptic terminals and dendritic profiles in the molecular layer of the cerebellum of a male patient aged 75 years, suffered from Alzheimer's disease. The disruption of the mitochondrial cristae is obvious. Electron micrograph (Mag.68,000 X).*

#### **Figure 3.**

*In the majority of the synaptic profiles the mitochondria are elongated demonstrating an impressive polymorphism, concerning the arrangement of the cristae. Mitochondria in a synaptic profile in the molecular layer of the cerebellum of a male patient aged 68, who suffered from Alzheimer's disease. Electron micrograph (Mag. 68,000X).*

**97**

**Figure 4.**

*73 years, (Mag. 28, 000 X).*

*Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target…*

A substantial number of mitochondria show disruption of the cristae, though others include osmiophilic material [10, 11, 13]. In the majority of the synaptic profiles, the mitochondria showed an impressive polymorphism, concerning the pattern and the arrangement of the cristae (**Figure 3**). That polymorphism was particularly obvious in dendritic profiles in acoustic and visual cortices, where morphological alterations of the mitochondria coexisted frequently with the fragmenta-

The ultrastructural study of the cerebellar cortex, in the vermis and the hemispheres, revealed impressive mitochondrial polymorphism in the soma of the neurons, the dendritic profiles (**Figure 5**), as well as in the axons and the synaptic

Besides, the electron microscopy study revealed that morphological alterations are frequently seen in neurons of the prefrontal cortex, which included mostly small round mitochondria, with an abnormal arrangement of the cristae (**Figure 7**). Abnormal polymorphic mitochondria in association with the fragmentation of the Golgi apparatus were also observed in the Purkinje cells of the cerebellar cortex in the vermis and the hemispheres [68], in the stellate cells of the molecular layer of the cerebellar cortex (**Figure 8**), as well as in a substantial number of neurons of the

By the morphological analysis of the mitochondria in the cortex of the brain hemispheres in Alzheimer's disease, it was realized that mitochondrial pathology

From the morphometric point of view, the ellipsoid mitochondria in normal controls appear to have an average diameter of 650 ± 250 nm and a mean axial ratio of 1.9 ± 0.2. The round or global mitochondria in normal controls appeared to have

*Mitochondrial polymorphism is obvious in neurons of the acoustic cortex, where morphological alterations of the mitochondria coexist frequently with the fragmentation of the Golgi apparatus. Electron micrograph of a neuron from the acoustic cortex of a female patient, who suffered from Alzheimer's disease at the age of* 

was associated as a rule with dendritic and spinal pathology [70].

*DOI: http://dx.doi.org/10.5772/intechopen.98436*

tion of the Golgi apparatus (**Figure 4**).

a mean mitochondrial radius of 350 nm.

terminals (**Figure 6**) [66, 67].

prefrontal cortex [69].

#### *Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target… DOI: http://dx.doi.org/10.5772/intechopen.98436*

A substantial number of mitochondria show disruption of the cristae, though others include osmiophilic material [10, 11, 13]. In the majority of the synaptic profiles, the mitochondria showed an impressive polymorphism, concerning the pattern and the arrangement of the cristae (**Figure 3**). That polymorphism was particularly obvious in dendritic profiles in acoustic and visual cortices, where morphological alterations of the mitochondria coexisted frequently with the fragmentation of the Golgi apparatus (**Figure 4**).

The ultrastructural study of the cerebellar cortex, in the vermis and the hemispheres, revealed impressive mitochondrial polymorphism in the soma of the neurons, the dendritic profiles (**Figure 5**), as well as in the axons and the synaptic terminals (**Figure 6**) [66, 67].

Besides, the electron microscopy study revealed that morphological alterations are frequently seen in neurons of the prefrontal cortex, which included mostly small round mitochondria, with an abnormal arrangement of the cristae (**Figure 7**). Abnormal polymorphic mitochondria in association with the fragmentation of the Golgi apparatus were also observed in the Purkinje cells of the cerebellar cortex in the vermis and the hemispheres [68], in the stellate cells of the molecular layer of the cerebellar cortex (**Figure 8**), as well as in a substantial number of neurons of the prefrontal cortex [69].

By the morphological analysis of the mitochondria in the cortex of the brain hemispheres in Alzheimer's disease, it was realized that mitochondrial pathology was associated as a rule with dendritic and spinal pathology [70].

From the morphometric point of view, the ellipsoid mitochondria in normal controls appear to have an average diameter of 650 ± 250 nm and a mean axial ratio of 1.9 ± 0.2. The round or global mitochondria in normal controls appeared to have a mean mitochondrial radius of 350 nm.

#### **Figure 4.**

*Cerebral and Cerebellar Cortex – Interaction and Dynamics in Health and Disease*

*Mitochondrial alterations in synaptic terminals and dendritic profiles in the molecular layer of the cerebellum of a male patient aged 75 years, suffered from Alzheimer's disease. The disruption of the mitochondrial cristae* 

*In the majority of the synaptic profiles the mitochondria are elongated demonstrating an impressive polymorphism, concerning the arrangement of the cristae. Mitochondria in a synaptic profile in the molecular layer of the cerebellum of a male patient aged 68, who suffered from Alzheimer's disease. Electron micrograph* 

**96**

**Figure 3.**

*(Mag. 68,000X).*

**Figure 2.**

*is obvious. Electron micrograph (Mag.68,000 X).*

*Mitochondrial polymorphism is obvious in neurons of the acoustic cortex, where morphological alterations of the mitochondria coexist frequently with the fragmentation of the Golgi apparatus. Electron micrograph of a neuron from the acoustic cortex of a female patient, who suffered from Alzheimer's disease at the age of 73 years, (Mag. 28, 000 X).*

In the brains of patients who suffered from Alzheimer's disease, the ellipsoid mitochondria of the neurons appeared to have an average diameter of 510 ± 250 nm and a mean axial ratio of 1.7 ± 0.2. The round mitochondria have had a mean radius of 280 nm. Also, the round mitochondria appeared to have a mean radius of 350 nm.

#### **Figure 5.**

*Very elongated mitochondrion in a dendritic profile in the mocelular layer of the vermis of a male patient aged 63 years, who suffered from Alzheimer's disease in the early stages. Electron micrograph (Mag. 128,000 X).*

#### **Figure 6.**

*Fragmentation of the cristae and impressive polymorphism of mitochondria in dendritic spines in the cortex of the cerebellar hemispheres of a male patient who suffered from Alzheimer's disease at the age of 75 years. Electron micrograph. Mag.135.000X).*

**99**

**Figure 8.**

**Figure 7.**

*(Mag. 28,000 X).*

*Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target…*

*Small mitochondria with abnormal arrangement of the cristae in a neuron from the prefrontal cortex of a male patient aged 75 years, who suffered from Alzheimer's disease in the early stages. Electron microgram* 

*Morphological alterations of mitochondria, coexist frequently with fragmentation of Golgi apparatus. Small compact mitochondria and fragmented cisternae of Golgi apparatus in the soma of an interneuron (stellate cell) of the molecular layer of the cerebellum of a male patient aged 63 years, who suffered from Alzheimer's* 

*disease in the early stages. Electron micrograph (Mag. 28,000 X).*

*DOI: http://dx.doi.org/10.5772/intechopen.98436*

*Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target… DOI: http://dx.doi.org/10.5772/intechopen.98436*

#### **Figure 7.**

*Cerebral and Cerebellar Cortex – Interaction and Dynamics in Health and Disease*

In the brains of patients who suffered from Alzheimer's disease, the ellipsoid mitochondria of the neurons appeared to have an average diameter of 510 ± 250 nm and a mean axial ratio of 1.7 ± 0.2. The round mitochondria have had a mean radius of 280 nm. Also, the round mitochondria appeared to have a mean radius

*Very elongated mitochondrion in a dendritic profile in the mocelular layer of the vermis of a male patient aged 63 years, who suffered from Alzheimer's disease in the early stages. Electron micrograph (Mag. 128,000 X).*

*Fragmentation of the cristae and impressive polymorphism of mitochondria in dendritic spines in the cortex of the cerebellar hemispheres of a male patient who suffered from Alzheimer's disease at the age of 75 years.* 

**98**

**Figure 6.**

*Electron micrograph. Mag.135.000X).*

of 350 nm.

**Figure 5.**

*Small mitochondria with abnormal arrangement of the cristae in a neuron from the prefrontal cortex of a male patient aged 75 years, who suffered from Alzheimer's disease in the early stages. Electron microgram (Mag. 28,000 X).*

#### **Figure 8.**

*Morphological alterations of mitochondria, coexist frequently with fragmentation of Golgi apparatus. Small compact mitochondria and fragmented cisternae of Golgi apparatus in the soma of an interneuron (stellate cell) of the molecular layer of the cerebellum of a male patient aged 63 years, who suffered from Alzheimer's disease in the early stages. Electron micrograph (Mag. 28,000 X).*

## **4. Discussion**

The morphological alteration of the mitochondria, which was extensively observed in the cortex of the brain hemispheres, the vermis and the hemispheres of the cerebellum pleads in favor of a generalized mitochondrial dysfunction in Alzheimer's disease, which would be associated with wide neuronal loss, impaired axoplasmic flow, dendritic pathology, and marked synaptic and spinal alterations, which would be seriously affecting the mental faculties of the patients [71].

The defective mitochondria in Alzheimer's neurons may not supply adequate levels of Adenosine Triphosphate (ATP), which is very important at the synaptic level for normal neural communication. It is expectable that the low levels of cellular ATP at nerve terminals may lead to extensive loss of synapses or cause defective function in the majority of them [72]. Besides, oxidative stress decreases the rate of choline recycling at the synapses, leading to Ach deficiency [73].

Many morphological alterations of AD could be linked to mitochondria changes since blockage of mitochondrial energy production shifts amyloid-protein precursor metabolism to the production of more amyloidogenic forms of amyloid [74]. Thus it induces the production of A68 antigen [75, 76], and activates the mitogenactivated protein kinase pathway [77–79].

Also, inadequate energy production impairs the mitochondrial motility in the soma, the axons, and the dendritic branches of neurons, resulting in trafficking jams aggravating even farther the mitochondrial function [80].

Accumulation also of transmembrane-arrested AβPP may block protein translocation, affecting, even more, the mitochondrial function. In a parallel way, the accumulated Aβ peptide in the mitochondrial membrane may be transported from the cytosol via mitochondrial translocases, which are located either in the outer or the inner mitochondrial membranes. Moreover, the Aβ peptide interacts with an Aβ-binding dehydrogenase (ABAD) in the mitochondria of patients suffering from Alzheimer's disease as well as in transgenic mice, suggesting that ABAD is closely related, to mitochondrial toxicity [81]. Overexpression of ABAD can increase oxidative stress, accelerating, therefore, neuronal death. However, ABAD may play an important role in the oxidation of alcohols, facilitating the reduction of aldehydes and ketones, and decreasing subsequently the metabolic stress [82].

The Aβ-peptide may interact with cyclophilin D (CypD), a component of the mitochondrial transition pore, inducing cytotoxicity [83]. Moreover, morphological alterations of mitochondria in AD may be related to the increased mitophagy, which is proved by the accumulation of mitochondrial autophagic elements in neurons of AD patients [84]. In AD the PINK1-Parkin-dependent mitophagy pathway may also be involved in mitochondrial pathology [85]. The prompt clearance of damaged mitochondria may result in increasing the density of normal mitochondria in dendrites and synaptic terminals, which is a fact ameliorating the synaptic function [86].

#### **5. Suggestions on the treatment of Alzheimer's disease on the basis of mitochondrial pathology**

Concerning the treatment of Alzheimer's disease, we would underline that the preclinical stage is frequently overlooked, because it might be characterized as mild cognitive impairment, with considerable consequences on the course and the treatment of the disease.

**101**

*Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target…*

tions and impede the clinical deterioration of the patients.

tive stress, and decrease ROS production [90].

of ROS, suppressing the oxidative stress.

including Alzheimer's disease [100].

Alzheimer's disease [102, 103].

patients who suffer from AD.

of AD [92].

Following the clinical manifestation of the disease and the diagnostic documentation, many therapeutic regimes have been applied without any substantial beneficial effect. In the decade 2002–2012 more than 240 drugs, mostly cholinesterase inhibitors, and NMDA receptor antagonists, have been tried for the treatment or even the amelioration of the quality of life in patients suffered from AD [87, 88], without any obvious effectiveness. Besides, any strategy attempting to reduce the amyloid aggregations in the brain, despite the numerous trials, was not fruitful [89]. Based on mitochondrial pathology, in the limits of the broad pathogenetic spectrum of Alzheimer's disease, the mitochondria may be considered as the potential therapeutic targets, which might inhibit the stream of the neuropathological altera-

Strategists protecting the mitochondria in Alzheimer's disease would include the administration of efficient antioxidant factors, which might counteract the oxida-

Natural antioxidants that could penetrate the blood–brain barrier may be effective in the initial stage of Alzheimer's disease. The administration of Vitamins C, E, beta carotene, glutathione, Coenzyme Q10, epigallocatechin gallate, curcumin, lipoic acid, *Ginkgo biloba*, resveratrol, pramipexole,

N-acetylcysteine, latrepirdine, idebenone, ubiquinone may reduce the production

In a parallel way, the adaptation of the Cretic or Mediterranean diet, combined

We have realized, by a detailed clinical and neuropsychological evaluation of a considerable number of patients, who suffered from Alzheimer's disease in the initial stages, that the quotidian administration of Riboflavin (Vit.B2) in a dose of 100–200 mg per day would play a positive role in inhibiting the course of the disease and stabilizing the mental faculties of the patients (Baloyannis, unpublished data). It is known that riboflavin serves as a flavoprotein precursor in the synthesis of flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) [94, 95], which are electrochemically-active factors involved in regulatory pathways of mitochondria. Riboflavin serves also as a cofactor in fatty acid β-oxidation. Riboflavin deficiency may be involved in the pathogenetic mechanism of several neurodegenerative disorders [96, 97]. Thus, riboflavin supplementation may be enriching the therapeutical regime in some non-uncommon neurological conditions [98, 99]

At the experimental level, mitochondrial-targeted molecules, such as MitoQ and Szeto- Schiller (SS) peptides have been used for increasing the concentration of antioxidants into mitochondria [101]. MitoQ exerts direct antioxidant action by scavenging superoxide, peroxyl, and peroxynitrite ROS. It seems also to contribute effectively, enhancing the mitochondrial biogenesis in a transgenic mouse model of

The fact that the interaction of ABAD with the Aβ peptide may increase the toxic

effects upon the mitochondria, suggests that ABAD inhibitors such as AG18051 [104] and RM-532-46, might be applied as therapeutic factors in the treatment of

with frequent proper physical exercise, in the early stages of the disease, may stabilize the mental capacities of the patients for a non-limited period and postpone the tragic epilogue of the disease. Besides, prolonged administration of pyruvate

may improve the working memory in the preclinical stage AD [93].

The tetracyclin Minocycline prevents also oxidative stress and controls the release of cytochrome c from mitochondria, inhibiting the activation of caspase-3 and the subsequent apoptosis [91], being therefore quite effective in the treatment

*DOI: http://dx.doi.org/10.5772/intechopen.98436*

#### *Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target… DOI: http://dx.doi.org/10.5772/intechopen.98436*

Following the clinical manifestation of the disease and the diagnostic documentation, many therapeutic regimes have been applied without any substantial beneficial effect. In the decade 2002–2012 more than 240 drugs, mostly cholinesterase inhibitors, and NMDA receptor antagonists, have been tried for the treatment or even the amelioration of the quality of life in patients suffered from AD [87, 88], without any obvious effectiveness. Besides, any strategy attempting to reduce the amyloid aggregations in the brain, despite the numerous trials, was not fruitful [89].

Based on mitochondrial pathology, in the limits of the broad pathogenetic spectrum of Alzheimer's disease, the mitochondria may be considered as the potential therapeutic targets, which might inhibit the stream of the neuropathological alterations and impede the clinical deterioration of the patients.

Strategists protecting the mitochondria in Alzheimer's disease would include the administration of efficient antioxidant factors, which might counteract the oxidative stress, and decrease ROS production [90].

Natural antioxidants that could penetrate the blood–brain barrier may be effective in the initial stage of Alzheimer's disease. The administration of Vitamins C, E, beta carotene, glutathione, Coenzyme Q10, epigallocatechin gallate, curcumin, lipoic acid, *Ginkgo biloba*, resveratrol, pramipexole, N-acetylcysteine, latrepirdine, idebenone, ubiquinone may reduce the production of ROS, suppressing the oxidative stress.

The tetracyclin Minocycline prevents also oxidative stress and controls the release of cytochrome c from mitochondria, inhibiting the activation of caspase-3 and the subsequent apoptosis [91], being therefore quite effective in the treatment of AD [92].

In a parallel way, the adaptation of the Cretic or Mediterranean diet, combined with frequent proper physical exercise, in the early stages of the disease, may stabilize the mental capacities of the patients for a non-limited period and postpone the tragic epilogue of the disease. Besides, prolonged administration of pyruvate may improve the working memory in the preclinical stage AD [93].

We have realized, by a detailed clinical and neuropsychological evaluation of a considerable number of patients, who suffered from Alzheimer's disease in the initial stages, that the quotidian administration of Riboflavin (Vit.B2) in a dose of 100–200 mg per day would play a positive role in inhibiting the course of the disease and stabilizing the mental faculties of the patients (Baloyannis, unpublished data). It is known that riboflavin serves as a flavoprotein precursor in the synthesis of flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) [94, 95], which are electrochemically-active factors involved in regulatory pathways of mitochondria. Riboflavin serves also as a cofactor in fatty acid β-oxidation. Riboflavin deficiency may be involved in the pathogenetic mechanism of several neurodegenerative disorders [96, 97]. Thus, riboflavin supplementation may be enriching the therapeutical regime in some non-uncommon neurological conditions [98, 99] including Alzheimer's disease [100].

At the experimental level, mitochondrial-targeted molecules, such as MitoQ and Szeto- Schiller (SS) peptides have been used for increasing the concentration of antioxidants into mitochondria [101]. MitoQ exerts direct antioxidant action by scavenging superoxide, peroxyl, and peroxynitrite ROS. It seems also to contribute effectively, enhancing the mitochondrial biogenesis in a transgenic mouse model of Alzheimer's disease [102, 103].

The fact that the interaction of ABAD with the Aβ peptide may increase the toxic effects upon the mitochondria, suggests that ABAD inhibitors such as AG18051 [104] and RM-532-46, might be applied as therapeutic factors in the treatment of patients who suffer from AD.

*Cerebral and Cerebellar Cortex – Interaction and Dynamics in Health and Disease*

choline recycling at the synapses, leading to Ach deficiency [73].

jams aggravating even farther the mitochondrial function [80].

activated protein kinase pathway [77–79].

The morphological alteration of the mitochondria, which was extensively observed in the cortex of the brain hemispheres, the vermis and the hemispheres of the cerebellum pleads in favor of a generalized mitochondrial dysfunction in Alzheimer's disease, which would be associated with wide neuronal loss, impaired axoplasmic flow, dendritic pathology, and marked synaptic and spinal alterations, which would be seriously affecting the mental faculties of the patients [71].

The defective mitochondria in Alzheimer's neurons may not supply adequate levels of Adenosine Triphosphate (ATP), which is very important at the synaptic level for normal neural communication. It is expectable that the low levels of cellular ATP at nerve terminals may lead to extensive loss of synapses or cause defective function in the majority of them [72]. Besides, oxidative stress decreases the rate of

Many morphological alterations of AD could be linked to mitochondria changes since blockage of mitochondrial energy production shifts amyloid-protein precursor metabolism to the production of more amyloidogenic forms of amyloid [74]. Thus it induces the production of A68 antigen [75, 76], and activates the mitogen-

Also, inadequate energy production impairs the mitochondrial motility in the soma, the axons, and the dendritic branches of neurons, resulting in trafficking

Accumulation also of transmembrane-arrested AβPP may block protein translocation, affecting, even more, the mitochondrial function. In a parallel way, the accumulated Aβ peptide in the mitochondrial membrane may be transported from the cytosol via mitochondrial translocases, which are located either in the outer or the inner mitochondrial membranes. Moreover, the Aβ peptide interacts with an Aβ-binding dehydrogenase (ABAD) in the mitochondria of patients suffering from Alzheimer's disease as well as in transgenic mice, suggesting that ABAD is closely related, to mitochondrial toxicity [81]. Overexpression of ABAD can increase oxidative stress, accelerating, therefore, neuronal death. However, ABAD may play an important role in the oxidation of alcohols, facilitating the reduction of aldehydes and ketones, and decreasing subsequently the metabolic

The Aβ-peptide may interact with cyclophilin D (CypD), a component of the mitochondrial transition pore, inducing cytotoxicity [83]. Moreover, morphological alterations of mitochondria in AD may be related to the increased mitophagy, which is proved by the accumulation of mitochondrial autophagic elements in neurons of AD patients [84]. In AD the PINK1-Parkin-dependent mitophagy pathway may also be involved in mitochondrial pathology [85]. The prompt clearance of damaged mitochondria may result in increasing the density of normal mitochondria in dendrites and synaptic terminals, which is a fact ameliorating the synaptic

**5. Suggestions on the treatment of Alzheimer's disease on the basis** 

Concerning the treatment of Alzheimer's disease, we would underline that the preclinical stage is frequently overlooked, because it might be characterized as mild cognitive impairment, with considerable consequences on the course and the treat-

**4. Discussion**

**100**

stress [82].

function [86].

ment of the disease.

**of mitochondrial pathology**

Also, a decrease of the CypD in AD relieves the toxic effect that Aβ imposes on the mitochondria and may ameliorate the mental condition of the patients [83] improving the synaptic function by the restoration of mitochondrial activity [105]. Also, Oligomycin-sensitivity conferring protein (OSCP) is a crucial subunit of mitochondrial F1Fo ATP synthase, essential for its structural stability [106]. In Alzheimer's disease, deregulation of mitochondrial F1FO-ATP synthase was described [107]. It is reasonable to be hypothesized that OSCP would be a positive factor in the treatment of early cases of Alzheimer's disease.

The administration of factors that may regulate mitophagy, and cardiolipininduced mitophagy [108] such as NAD+ precursors, actinonin (AC), spermidine, urolithin A (UA), rapamycin, and doxycycline may also control the mitochondrial unfolded protein response (UPRmt), reducing the Aβ accumulation and proteotoxicity [109].

The administration of metformin can increase also the resistance of the mitochondria to oxidative stress [110]. The supplementation with nicotinamide may be beneficial in the early stages of Alzheimer's disease improving the cognition of the patients [111].

The administration of mitochondrial uncoupling factors such as 2, 4-dinitrophenol (DNP) may be effective too, protecting mitochondria and stabilizing neuronal function in animal models of AD [112, 113]. Besides, the administration of galanthamine hydrochloride may control autophagy [114], as was noticed by the decrease of autophagosome formation.

Recently it was found that vacuole membrane protein 1 (VMP1), which is located in the endoplasmic reticulum (ER), may play a crucial role in mediating autophagy [115] and controlling mitochondrial morphology, given that numerous mitochondria are damaged upon VMP1 deficiency [116]. It must be underlined that autophagy is an important mechanism for maintaining cell homeostasis by liberating the cell from the accumulation of misfolded proteins and other undesired elements [117].

Erythropoietin (EPO) [118], is a cytokine essential for erythroid development and maturation, playing a beneficial role in progressive degenerative diseases [119] exercising among others a protective effect on mitochondrial morphology, facilitating the activity of cellular bioenergetics [120].

Furthermore, the relation between mitochondria and endoplasmic reticulum (ER) referred to as the MAMs [121, 122], which are enriched in presenilin proteins [123], may play an important role in the pathogenetic cascade of Alzheimer's disease, given that they are involved in the production of intracellular Aβ [124], and play also a substantial role in cellular Calcium homeostasis [125, 126] and lipid transport between the endoplasmic reticulum and the mitochondria [127]. A deep understanding of MAMs involvement in the pathogenesis of AD may provide new ways of therapeutic approach in the early stages of AD.

The protection of mitochondria by the Szeto-Schiller (SS) peptides, particularly the SS31 tetra-peptide [128, 129], which is targeted to the inner mitochondrial membrane, revealed that it may have protective effects against mitochondrial and synaptic toxicities in APP transgenic mice [130], reducing also mitochondrial fragmentation and increasing mitochondrial transport in AD neurons [131].

Mitochondrial biogenesis is decreased in AD [132] due to the decrease of the rate of mitochondrial division, a fact that aggravates substantially the mitochondrial dysfunction [133]. Supporting mitochondrial biogenesis may contribute to the therapeutic confrontation of AD [134]. Therefore, the administration of Nicotinamide riboside [135, 136], as well as of pioglitazone or rosiglitazone may improve the mental condition of the patients [137, 138].

**103**

*Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target…*

the frequent sleep and metabolic disorders of the patients [142].

be among the principal therapeutic strategists in AD.

In experimental models, the administration of melatonin contributed considerably to improving the biogenesis of mitochondria [139]. Besides, melatonin inhibits amyloidogenesis and promotes the non-amyloidogenic pathway [140], restoring also the equilibrium of the Ca2+ [141]. Recent neuropathological findings revealed that melanin-concentrating hormone (MCH) neurons in the lateral hypothalamic area of patients who suffer from AD undergo degeneration, a fact that may interpret

Also, it was observed, that the Zinc ion (Zn2+) supplementation in experimental models, contributed to ameliorating the mitochondrial function by the restoration of BDNF levels and improving cognition, although it might have negative effects on

Α substantial body of evidence suggests that among the causative factors in the multifactorial labyrinth of AD, the hemodynamic disturbances resulting in chronic hypoperfusion of the brain [144–147] play also a crucial role in attenuating the mitochondrial dysfunction [148] and aggravating subsequently the mental condition of the patients [149]. The improvement of the blood supply of the brain should

Mitochondrial alterations may be estimated as potential biomarkers, which would provide a prognostic response to treatment [150]. Mitochondria may be considered as a significant strategic point for therapeutical interventions in early

Mitochondrial alterations may play an important role in the pathogenesis of Alzheimer's disease. In early cases of Alzheimer's disease marked morphological and morphometric alterations have been described by electron microscopy in vari-

The morphological alterations of the mitochondria seem to be independent of Alzheimer's pathology, given that they are observed in areas without or with

Mitochondria may be considered as a significant strategic point for therapeutical

*DOI: http://dx.doi.org/10.5772/intechopen.98436*

some cells lines [143].

cases of Alzheimer's disease.

ous areas of the brain and the cerebellum.

minimal neuritic plaques or tau pathology.

interventions in early cases of Alzheimer's disease.

The author declares no conflict of interest.

**6. Conclusions**

**Conflict of interest**

*Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target… DOI: http://dx.doi.org/10.5772/intechopen.98436*

In experimental models, the administration of melatonin contributed considerably to improving the biogenesis of mitochondria [139]. Besides, melatonin inhibits amyloidogenesis and promotes the non-amyloidogenic pathway [140], restoring also the equilibrium of the Ca2+ [141]. Recent neuropathological findings revealed that melanin-concentrating hormone (MCH) neurons in the lateral hypothalamic area of patients who suffer from AD undergo degeneration, a fact that may interpret the frequent sleep and metabolic disorders of the patients [142].

Also, it was observed, that the Zinc ion (Zn2+) supplementation in experimental models, contributed to ameliorating the mitochondrial function by the restoration of BDNF levels and improving cognition, although it might have negative effects on some cells lines [143].

Α substantial body of evidence suggests that among the causative factors in the multifactorial labyrinth of AD, the hemodynamic disturbances resulting in chronic hypoperfusion of the brain [144–147] play also a crucial role in attenuating the mitochondrial dysfunction [148] and aggravating subsequently the mental condition of the patients [149]. The improvement of the blood supply of the brain should be among the principal therapeutic strategists in AD.

Mitochondrial alterations may be estimated as potential biomarkers, which would provide a prognostic response to treatment [150]. Mitochondria may be considered as a significant strategic point for therapeutical interventions in early cases of Alzheimer's disease.

### **6. Conclusions**

*Cerebral and Cerebellar Cortex – Interaction and Dynamics in Health and Disease*

factor in the treatment of early cases of Alzheimer's disease.

proteotoxicity [109].

of autophagosome formation.

ing the activity of cellular bioenergetics [120].

ways of therapeutic approach in the early stages of AD.

and increasing mitochondrial transport in AD neurons [131].

improve the mental condition of the patients [137, 138].

patients [111].

elements [117].

Also, a decrease of the CypD in AD relieves the toxic effect that Aβ imposes on the mitochondria and may ameliorate the mental condition of the patients [83] improving the synaptic function by the restoration of mitochondrial activity [105]. Also, Oligomycin-sensitivity conferring protein (OSCP) is a crucial subunit of mitochondrial F1Fo ATP synthase, essential for its structural stability [106]. In Alzheimer's disease, deregulation of mitochondrial F1FO-ATP synthase was described [107]. It is reasonable to be hypothesized that OSCP would be a positive

The administration of factors that may regulate mitophagy, and cardiolipininduced mitophagy [108] such as NAD+ precursors, actinonin (AC), spermidine, urolithin A (UA), rapamycin, and doxycycline may also control the mitochondrial unfolded protein response (UPRmt), reducing the Aβ accumulation and

The administration of metformin can increase also the resistance of the mitochondria to oxidative stress [110]. The supplementation with nicotinamide may be beneficial in the early stages of Alzheimer's disease improving the cognition of the

The administration of mitochondrial uncoupling factors such as 2, 4-dinitrophenol (DNP) may be effective too, protecting mitochondria and stabilizing neuronal function in animal models of AD [112, 113]. Besides, the administration of galanthamine hydrochloride may control autophagy [114], as was noticed by the decrease

Recently it was found that vacuole membrane protein 1 (VMP1), which is located in the endoplasmic reticulum (ER), may play a crucial role in mediating autophagy [115] and controlling mitochondrial morphology, given that numerous mitochondria are damaged upon VMP1 deficiency [116]. It must be underlined that autophagy is an important mechanism for maintaining cell homeostasis by liberating the cell from the accumulation of misfolded proteins and other undesired

Erythropoietin (EPO) [118], is a cytokine essential for erythroid development and maturation, playing a beneficial role in progressive degenerative diseases [119] exercising among others a protective effect on mitochondrial morphology, facilitat-

Furthermore, the relation between mitochondria and endoplasmic reticulum (ER) referred to as the MAMs [121, 122], which are enriched in presenilin proteins [123], may play an important role in the pathogenetic cascade of Alzheimer's disease, given that they are involved in the production of intracellular Aβ [124], and play also a substantial role in cellular Calcium homeostasis [125, 126] and lipid transport between the endoplasmic reticulum and the mitochondria [127]. A deep understanding of MAMs involvement in the pathogenesis of AD may provide new

The protection of mitochondria by the Szeto-Schiller (SS) peptides, particularly the SS31 tetra-peptide [128, 129], which is targeted to the inner mitochondrial membrane, revealed that it may have protective effects against mitochondrial and synaptic toxicities in APP transgenic mice [130], reducing also mitochondrial fragmentation

Mitochondrial biogenesis is decreased in AD [132] due to the decrease of the rate of mitochondrial division, a fact that aggravates substantially the mitochondrial dysfunction [133]. Supporting mitochondrial biogenesis may contribute to the therapeutic confrontation of AD [134]. Therefore, the administration of Nicotinamide riboside [135, 136], as well as of pioglitazone or rosiglitazone may

**102**

Mitochondrial alterations may play an important role in the pathogenesis of Alzheimer's disease. In early cases of Alzheimer's disease marked morphological and morphometric alterations have been described by electron microscopy in various areas of the brain and the cerebellum.

The morphological alterations of the mitochondria seem to be independent of Alzheimer's pathology, given that they are observed in areas without or with minimal neuritic plaques or tau pathology.

Mitochondria may be considered as a significant strategic point for therapeutical interventions in early cases of Alzheimer's disease.

#### **Conflict of interest**

The author declares no conflict of interest.

*Cerebral and Cerebellar Cortex – Interaction and Dynamics in Health and Disease*

## **Author details**

Stavros J. Baloyannis Department of Neurology, Aristotelian University of Thessaloniki, Thessaloniki, Greece

\*Address all correspondence to: sibh844@otenet.gr

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**105**

*Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target…*

[10] Baloyannis S. Mitochondrial alterations in Alzheimer's Disease. Neurobiol. Aging. 1998; 19: S241.

[11] Baloyannis SJ. Mitochondrial alterations in Alzheimer's disease. J. Alzh. Dis. 2006; 9: 119– 126.

[13] Baloyannis S. Mitochondrial alterations in neurons of various areas of the brain in Parkinson's disease: an

Parkinsonism and Related disorders.

[14] Tucker D, Lu Y, Zhang Q. From

Neuroprotection-an Emerging Role for Methylene Blue. Mol. Neurobiol. 2018,

[15] Cardoso S, Carvalho C, Correia S C, Seiça RM, Moreira PI. Alzheimer's disease: From mitochondrial perturbations to mitochondrial medicine. Brain Pathol. 2016; 26:

electron microscopy study.

Mitochondrial Function to

[16] Bertholet AM, Delerue T, Millet AM, Moulis MF, David C, Daloyau M, Belenguer P. Mitochondrial

fusion/fission dynamics in neurodegeneration and neuronal plasticity. Neurobiol. Dis. 2016; 90:

[17] Rodolfo C, Campello S, Cecconi F. Mitophagy in neurodegenerative diseases. Neurochem. Internatl. 2017;

mitochondrial motility in neurons. Curr.

[18] Barnhart EL. Mechanics of

Opin. Cell Biol. 2016; 38: 90– 99.

2001; 7: S10.

55,137-153.

632– 647.

3– 19.

117: 156– 166.

2014; 1842: 1219-1231.

[12] Swerdlow RH, Burns JM, Khan SM. The Alzheimer's disease mitochondrial cascade hypothesis: Progress and perspectives. Biochim. Biophys. Acta.

*DOI: http://dx.doi.org/10.5772/intechopen.98436*

[1] Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: A systematic review and meta-analysis. Alzheimers Dement. 2013; 9: 63– 75 e2.

[2] Terry R. The pathogenesis of

Arnaoutoglou A, Arnaoutoglou H. Synaptic alterations in the molecular layer of the cerebellum in Alzheimer's disease. Neuropath. Appl. Neurobiol.

[4] Baloyannis S, Costa V. Αbnormal synapses in the granule cell layer of the cerebellum in Alzheimer's disease: A Golgi and Electron microscope study. European J. Neurol. 1998; 5: 26-27.

[5] Braak H, Braak E. Staging of Alzheimer's disease-related

Aging. 1995; 16: 271– 278.

neurofibrillary changes. Neurobiol.

[6] Morris M, Maeda S, Vossel K, Mucke L. The many faces of tau. Neuron, 2011; 70: 410– 426.

[7] Crass P, Kawai M, Siedlak S, Mulvihill P, Gambetti P, Loweryd D, Gonzalez De Whitt P, Greenberg B, Perry G. Neuronal and microglial involvement in β amyloid protein deposition in Alzheimer's disease. Am. J.

Pathol. 1990; 37: 241 246.

Science. 1992; 256: 184– 185.

[9] Drachman DA. The amyloid

[8] Hardy J A, Higgins GA. Alzheimer's disease: The amyloid cascade hypothesis.

hypothesis, time to move on: Amyloid is the downstream result, not cause, of Alzheimer's disease. Alzheimers Dement. 2014; 10: 372– 380.

[3] Baloyannis S, Costa V,

1996; 22: 78-79.

**References**

Alzheimer disease: An alternative to the amyloid hypothesis. J. Neuropathology Exper. Neurology. 1996; 55: 1023-1025.

*Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target… DOI: http://dx.doi.org/10.5772/intechopen.98436*

## **References**

*Cerebral and Cerebellar Cortex – Interaction and Dynamics in Health and Disease*

**104**

**Author details**

Stavros J. Baloyannis

Thessaloniki, Greece

Department of Neurology, Aristotelian University of Thessaloniki,

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: sibh844@otenet.gr

provided the original work is properly cited.

[1] Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: A systematic review and meta-analysis. Alzheimers Dement. 2013; 9: 63– 75 e2.

[2] Terry R. The pathogenesis of Alzheimer disease: An alternative to the amyloid hypothesis. J. Neuropathology Exper. Neurology. 1996; 55: 1023-1025.

[3] Baloyannis S, Costa V, Arnaoutoglou A, Arnaoutoglou H. Synaptic alterations in the molecular layer of the cerebellum in Alzheimer's disease. Neuropath. Appl. Neurobiol. 1996; 22: 78-79.

[4] Baloyannis S, Costa V. Αbnormal synapses in the granule cell layer of the cerebellum in Alzheimer's disease: A Golgi and Electron microscope study. European J. Neurol. 1998; 5: 26-27.

[5] Braak H, Braak E. Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiol. Aging. 1995; 16: 271– 278.

[6] Morris M, Maeda S, Vossel K, Mucke L. The many faces of tau. Neuron, 2011; 70: 410– 426.

[7] Crass P, Kawai M, Siedlak S, Mulvihill P, Gambetti P, Loweryd D, Gonzalez De Whitt P, Greenberg B, Perry G. Neuronal and microglial involvement in β amyloid protein deposition in Alzheimer's disease. Am. J. Pathol. 1990; 37: 241 246.

[8] Hardy J A, Higgins GA. Alzheimer's disease: The amyloid cascade hypothesis. Science. 1992; 256: 184– 185.

[9] Drachman DA. The amyloid hypothesis, time to move on: Amyloid is the downstream result, not cause, of Alzheimer's disease. Alzheimers Dement. 2014; 10: 372– 380.

[10] Baloyannis S. Mitochondrial alterations in Alzheimer's Disease. Neurobiol. Aging. 1998; 19: S241.

[11] Baloyannis SJ. Mitochondrial alterations in Alzheimer's disease. J. Alzh. Dis. 2006; 9: 119– 126.

[12] Swerdlow RH, Burns JM, Khan SM. The Alzheimer's disease mitochondrial cascade hypothesis: Progress and perspectives. Biochim. Biophys. Acta. 2014; 1842: 1219-1231.

[13] Baloyannis S. Mitochondrial alterations in neurons of various areas of the brain in Parkinson's disease: an electron microscopy study. Parkinsonism and Related disorders. 2001; 7: S10.

[14] Tucker D, Lu Y, Zhang Q. From Mitochondrial Function to Neuroprotection-an Emerging Role for Methylene Blue. Mol. Neurobiol. 2018, 55,137-153.

[15] Cardoso S, Carvalho C, Correia S C, Seiça RM, Moreira PI. Alzheimer's disease: From mitochondrial perturbations to mitochondrial medicine. Brain Pathol. 2016; 26: 632– 647.

[16] Bertholet AM, Delerue T, Millet AM, Moulis MF, David C, Daloyau M, Belenguer P. Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity. Neurobiol. Dis. 2016; 90: 3– 19.

[17] Rodolfo C, Campello S, Cecconi F. Mitophagy in neurodegenerative diseases. Neurochem. Internatl. 2017; 117: 156– 166.

[18] Barnhart EL. Mechanics of mitochondrial motility in neurons. Curr. Opin. Cell Biol. 2016; 38: 90– 99.

[19] Seo AY, Joseph AM, Dutta D, Hwang JC, Aris JP, Leeuwenburgh C. New insights into the role of mitochondria in aging: Mitochondrial dynamics and more. J. Cell Sci. 2010; 123: 2533– 2542.

[20] Sandhir R, Halder A, Sunkaria A. Mitochondria as a centrally positioned hub in the innate immune response. Biochim. Biophys. Acta Mol. Basis Dis. 2017; 1863: 1090-1097.

[21] Jacobs JL, Coyne CB. Mechanisms of MAVS regulation at the mitochondrial membrane. J. Mol. Biol. 2013; 425: 5009-5019.

[22] West AP, Shadel GS, Ghosh S. Mitochondria in innate immune responses. Nat. Rev. Immunol. 2011; 11: 389-402.

[23] Rimessi A, Previati M, Nigro F, Wieckowski MR, Pinton P. Mitochondrial reactive oxygen species and inflammation: Molecular mechanisms, diseases and promising therapies. Int. J. Biochem. Cell Biol. 2016; 81: 281-293.

[24] Wang X, Wang W, Li L, Perry G, Lee HG, Zhu X. Oxidative stress and mitochondrial dysfunction in Alzheimer's disease. Bioch. Biophys. Acta. 2014; 1842: 1240– 1247.

[25] Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA. Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol. 2001;60:759-767.

[26] Guo C, Sun L, Chen X, Zhang D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural. Regen. Res. 2013; 8:2003-2014.

[27] Birnbaum JH, Wanner D, Gietl AF, Saake A, Kündig TM, Hock C,

Nitsch RM, Tackenberg C. Oxidative stress and altered mitochondrial protein expression in the absence of amyloid-β and tau pathology in iPSC-derived neurons from sporadic Alzheimer's disease patients. Stem Cell Res. 2018; 27:121-130.

[28] Hirai K, Aliev G, Nunomura A, Fujioka H, Russell R, Atwood C, Johnson A, Kress Y, Vinters H, Tabaton M, Shimohama S, Cash A, Siedlak S, Harris P, Jones P, Petersen R, Perry G, Smith M. Mitochondrial Abnormalities in Alzheimer's Disease. J. Neurosci. 2001; 21: 3017-3023.

[29] Baloyannis S, Costa V, Michmizos D. Mitochondrial alterations in Alzheimer's Disease. Am. J. Alzheimers Dis. Other Demen. 2004; 19: 89-93.

[30] Mizuno Y, Ikebe S, Hattori N, Nakagawa-Hattori, Y, Mochizuki H, Tanaka M, Ozawa Y. Role of mitochondria in the etiology and pathogenesis of Parkinson's disease. Bioch. Biophys. Acta. 1995; 1271: 265-274.

[31] Margineantu D, Cox W, Sundell L, Sherwood S, Beechem J, Capaldi R. Cell cycle dependent morphology changes and associated mtDNA redistribution in mitochondria of human cell lines. Mitochondrion. 2002; 1: 425-435.

[32] Mathew A, Lindsley TA, Sheridan A, Bhoiwala DL, Hushmendy SF, Yager EJ, Ruggiero EA, Crawford DR. Degraded mitochondrial DNA is a newly identified subtype of the damage associated molecular pattern (DAMP) family and possible trigger of neurodegeneration. J. Alzheimers Dis. 2012; 30: 617-627.

[33] Khodorov B, Pinelis V, Vergun O, Storozhevykh T, Vinskaya N. Mitochondrial deenergization underlies neuronal calcium overload following a prolonged glutamate challenge. FEBS Lett. 1996; 397: 230-234.

**107**

371-376.

*Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target…*

[41] Angelova PR, Abramov AY. Role of mitochondrial ROS in the brain: from physiology to neurodegeneration. FEBS

McQuibban GA, Kim, P.K. ROS-induced mitochondrial depolarization initiates

Letters. 2018; 92: 692-702.

[42] Wang Y, Nartiss Y, Steipe B,

PARK2/PARKIN-dependent mitochondrial degradation by autophagy. Autophagy. 2012, 8,

[43] Ristow M, Schmeisser K.

[45] Shadel GS, Horvath TL. Mitochondrial ROS signaling in

Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS). Dose Response.

[44] Schroder K, Zhou R, Tschopp J. The NLRP3 inflammasome: A sensor for metabolic danger? Science. 2010; 327:

organismal homeostasis. Cell. 2015; 163:

[46] Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, Ramanujan VK, Wolf AJ, Vergnes L, Ojcius DM, Rentsendorj A, Vargas M, Guerrero C, Wang Y, Fitzgerald KA, Underhill DM, Town T, Arditi M. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 2012;36:401-314.

[47] Manczak M, Reddy PH. Abnormal interaction of VDAC1 with amyloid beta

Alzheimer's disease. Human Molecular

[48] Perez MJ, Vergara- Pulgar K, Jara C, Cabezas- Opazo F, Quintanilla RA. Caspase- cleaved tau impairs

mitochondrial dynamics in Alzheimer's disease. Mol. Neurobiol. 2018; 55:

and phosphorylated tau causes mitochondrial dysfunction in

Genetics. 2012; 21: 5131– 5146.

1004-1018.

1462-1476.

296-300.

560-569.

2014; 12: 288-341.

*DOI: http://dx.doi.org/10.5772/intechopen.98436*

[34] Duchen M. Contributions of mitochondria to animal physiology: from homeostatic sensor to calcium signaling and cell death. J. Physiol.

[35] Morais Cardoso S, Swerdlow R, Oliveira C. Induction of cytochrome c-mediated apoptosis by amyloid beta 25-35 requires functional mitochondria.

[36] Moreira P, Santos M, Moreno A, Oliveira C. Amyloid beta-peptide promotes permeability transition pore in brain mitochondria. Biosci. Res. 2001;

[37] Pereira C, Santos M, Oliveira C. Involvement of oxidative stress on the impairment of energy metabolism induced by A beta peptides on PC12 cells: protection by antioxidants. Neurobiol. Dis. 1999; 6: 209-219.

[38] Arias C, Montiel T, Quiroz-Baez R, Massieu L. beta-Amyloid neurotoxicity

impairment in the rat hippocampus in vivo and in isolated nerve terminals: implications for Alzheimer's disease. Exp. Neurol. 2002; 176: 163-174.

is exacerbated during glycolysis inhibition and mitochondrial

[39] Crouch P, Blake, R.; Duce, J.; Ciccotosto, G.; Li, Q.; Barmham, K.; Curtain, C.; Cherny, R.; Cappai R, Dyrks T, Masters C, Trounce I. Copperdependent inhibition of human cytochrome c oxidase by dimeric conformer of amyloid-1-42. J. Neurosci.

[40] Bosetti F, Brizzi F, Barogi S, Mancuso M, Siciliano G, Tendi E, Murri L, Rapoport SI, Solaini G. Cytochrome c oxidase and

mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer's disease. Neurobiol. Aging. 2002; 23:

2005; 25: 672-679.

Brain Res. 2002; 931: 117-125.

21: 789-800.

(Lond). 1999; 516: 1-17.

*Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target… DOI: http://dx.doi.org/10.5772/intechopen.98436*

[34] Duchen M. Contributions of mitochondria to animal physiology: from homeostatic sensor to calcium signaling and cell death. J. Physiol. (Lond). 1999; 516: 1-17.

*Cerebral and Cerebellar Cortex – Interaction and Dynamics in Health and Disease*

Nitsch RM, Tackenberg C. Oxidative stress and altered mitochondrial protein expression in the absence of amyloid-β and tau pathology in iPSC-derived neurons from sporadic Alzheimer's disease patients. Stem Cell Res. 2018;

[28] Hirai K, Aliev G, Nunomura A, Fujioka H, Russell R, Atwood C, Johnson A, Kress Y, Vinters H, Tabaton M, Shimohama S, Cash A, Siedlak S, Harris P, Jones P, Petersen R, Perry G, Smith M. Mitochondrial Abnormalities in Alzheimer's Disease. J.

Neurosci. 2001; 21: 3017-3023.

[30] Mizuno Y, Ikebe S, Hattori N, Nakagawa-Hattori, Y, Mochizuki H,

[31] Margineantu D, Cox W, Sundell L, Sherwood S, Beechem J, Capaldi R. Cell cycle dependent morphology changes and associated mtDNA redistribution in mitochondria of human cell lines. Mitochondrion. 2002; 1: 425-435.

Hushmendy SF, Yager EJ, Ruggiero EA, Crawford DR. Degraded mitochondrial DNA is a newly identified subtype of the damage associated molecular pattern (DAMP) family and possible trigger of neurodegeneration. J. Alzheimers Dis. 2012; 30: 617-627.

[33] Khodorov B, Pinelis V, Vergun O,

Mitochondrial deenergization underlies neuronal calcium overload following a prolonged glutamate challenge. FEBS

Storozhevykh T, Vinskaya N.

Lett. 1996; 397: 230-234.

Tanaka M, Ozawa Y. Role of mitochondria in the etiology and pathogenesis of Parkinson's disease. Bioch. Biophys. Acta. 1995; 1271:

[32] Mathew A, Lindsley TA, Sheridan A, Bhoiwala DL,

265-274.

Demen. 2004; 19: 89-93.

[29] Baloyannis S, Costa V, Michmizos D. Mitochondrial alterations in Alzheimer's Disease. Am. J. Alzheimers Dis. Other

27:121-130.

[19] Seo AY, Joseph AM, Dutta D, Hwang JC, Aris JP, Leeuwenburgh C.

mitochondria in aging: Mitochondrial dynamics and more. J. Cell Sci. 2010;

[20] Sandhir R, Halder A, Sunkaria A. Mitochondria as a centrally positioned hub in the innate immune response. Biochim. Biophys. Acta Mol. Basis Dis.

[21] Jacobs JL, Coyne CB. Mechanisms of MAVS regulation at the mitochondrial membrane. J. Mol. Biol. 2013; 425:

[22] West AP, Shadel GS, Ghosh S. Mitochondria in innate immune responses. Nat. Rev. Immunol. 2011; 11:

[23] Rimessi A, Previati M, Nigro F,

Mitochondrial reactive oxygen species

mechanisms, diseases and promising therapies. Int. J. Biochem. Cell Biol.

[24] Wang X, Wang W, Li L, Perry G, Lee HG, Zhu X. Oxidative stress and mitochondrial dysfunction in Alzheimer's disease. Bioch. Biophys.

[25] Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA. Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol.

[26] Guo C, Sun L, Chen X, Zhang D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural.

[27] Birnbaum JH, Wanner D, Gietl AF,

Regen. Res. 2013; 8:2003-2014.

Saake A, Kündig TM, Hock C,

Wieckowski MR, Pinton P.

2016; 81: 281-293.

2001;60:759-767.

and inflammation: Molecular

Acta. 2014; 1842: 1240– 1247.

New insights into the role of

123: 2533– 2542.

2017; 1863: 1090-1097.

5009-5019.

389-402.

**106**

[35] Morais Cardoso S, Swerdlow R, Oliveira C. Induction of cytochrome c-mediated apoptosis by amyloid beta 25-35 requires functional mitochondria. Brain Res. 2002; 931: 117-125.

[36] Moreira P, Santos M, Moreno A, Oliveira C. Amyloid beta-peptide promotes permeability transition pore in brain mitochondria. Biosci. Res. 2001; 21: 789-800.

[37] Pereira C, Santos M, Oliveira C. Involvement of oxidative stress on the impairment of energy metabolism induced by A beta peptides on PC12 cells: protection by antioxidants. Neurobiol. Dis. 1999; 6: 209-219.

[38] Arias C, Montiel T, Quiroz-Baez R, Massieu L. beta-Amyloid neurotoxicity is exacerbated during glycolysis inhibition and mitochondrial impairment in the rat hippocampus in vivo and in isolated nerve terminals: implications for Alzheimer's disease. Exp. Neurol. 2002; 176: 163-174.

[39] Crouch P, Blake, R.; Duce, J.; Ciccotosto, G.; Li, Q.; Barmham, K.; Curtain, C.; Cherny, R.; Cappai R, Dyrks T, Masters C, Trounce I. Copperdependent inhibition of human cytochrome c oxidase by dimeric conformer of amyloid-1-42. J. Neurosci. 2005; 25: 672-679.

[40] Bosetti F, Brizzi F, Barogi S, Mancuso M, Siciliano G, Tendi E, Murri L, Rapoport SI, Solaini G. Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer's disease. Neurobiol. Aging. 2002; 23: 371-376.

[41] Angelova PR, Abramov AY. Role of mitochondrial ROS in the brain: from physiology to neurodegeneration. FEBS Letters. 2018; 92: 692-702.

[42] Wang Y, Nartiss Y, Steipe B, McQuibban GA, Kim, P.K. ROS-induced mitochondrial depolarization initiates PARK2/PARKIN-dependent mitochondrial degradation by autophagy. Autophagy. 2012, 8, 1462-1476.

[43] Ristow M, Schmeisser K. Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS). Dose Response. 2014; 12: 288-341.

[44] Schroder K, Zhou R, Tschopp J. The NLRP3 inflammasome: A sensor for metabolic danger? Science. 2010; 327: 296-300.

[45] Shadel GS, Horvath TL. Mitochondrial ROS signaling in organismal homeostasis. Cell. 2015; 163: 560-569.

[46] Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, Ramanujan VK, Wolf AJ, Vergnes L, Ojcius DM, Rentsendorj A, Vargas M, Guerrero C, Wang Y, Fitzgerald KA, Underhill DM, Town T, Arditi M. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 2012;36:401-314.

[47] Manczak M, Reddy PH. Abnormal interaction of VDAC1 with amyloid beta and phosphorylated tau causes mitochondrial dysfunction in Alzheimer's disease. Human Molecular Genetics. 2012; 21: 5131– 5146.

[48] Perez MJ, Vergara- Pulgar K, Jara C, Cabezas- Opazo F, Quintanilla RA. Caspase- cleaved tau impairs mitochondrial dynamics in Alzheimer's disease. Mol. Neurobiol. 2018; 55: 1004-1018.

[49] Correia SC, Moreira PI, Perry G. Unraveling the Role of Mitochondria in Alzheimer's Disease In: Vascular Disease, Alzheimer's Disease, and Mild Cognitive Impairment. Edited by: David J. Libon, Melissa Lamar, Rodney A. Swenson, Kenneth M. Heilman, Oxford University Press. 2020. DOI: 10.1093/oso/9780190634230. 003.0017.

[50] Ni HM,Williams JA, Ding WX. Mitochondrial dynamics and mitochondrial quality control. Redox Biol. 2015; 4; 6-13.

[51] Bereiter-Hahn J, Vöth M. Dynamic of mitochondria in living cells: shape changes, dislocations, fusion, and fission of mitochondria. Microsc. Res. Tech. 1994; 27: 198-219.

[52] Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood C S, et al. Mitochondrial abnormalities in Alzheimer's disease. J. Neurosci. 2001; 21: 3017– 3023.

[53] Baloyannis SJ, Costa V, Michmizos D. Mitochondrial alterations in Alzheimer's disease. Am. J. Alzheimers Dis. Other Demen. 2004; 19: 89-93.

[54] Baloyannis SJ, Manolides SL, Manolides LS. Dendritic and spinal pathology in the acoustic cortex in Alzheimer's disease: morphological estimation in Golgi technique and electron microscopy. Acta Otolaryngol. 2011; 131: 610-612.

[55] Manczak M, Reddy PH. Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons: Implications for mitochondrial dysfunction and neuronal damage. Hum. Mol. Genet. 2012; 21: 2538– 2547.

[56] Lin MY, Sheng ZH. Regulation of mitochondrial transport in neurons. Exper. Cell Res. 2015; 334: 35-44.

[57] Shahpasand K, Uemura I, Saito T, Asano T, Hata K, Shibata K, Hisanaga S. Regulation of mitochondrial transport and inter- microtubule spacing by tau phosphorylation at the sites hyperphosphorylated in Alzheimer's disease. J. Neurosci. 2012; 32:2430-2441.

[58] Baloyannis SJ. Dendritic pathology in Alzheimer's disease. J. Neurol. Sci. 2009; 283: 153-157.

[59] Baloyannis SJ, Mauroudis I, Manolides SL, Manolides LS. Synaptic alterations in the medial geniculate bodies and the inferior colliculi in Alzheimer's disease: a Golgi and electron microscope study. Acta Otolaryngol. 2009; 129:416-418.

[60] Quintanilla RA, Dolan PJ, Jin YN, Johnson GVW. Truncated tau and Abeta cooperatively impair mitochondria in primary neurons. Neurobiol. Aging. 2012; 33: 619 e25-35.

[61] Baloyannis SJ. Golgi apparatus and protein trafficking in Alzheimer's disease. J. Alzheimers Dis. 2014; 42 (Suppl 3):S153-162. doi: 10.3233/ JAD-132660. PMID: 24946873.

[62] Baloyannis SJ, Mavroudis I, Baloyannis JS, Costa VG. Mammillary Bodies in Alzheimer's Disease: A Golgi and Electron Microscope Study. Am. J. Alzheimers Dis. Other Demen. 2016; 31: 247-256.

[63] McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of department of health and human services task force on Alzheimer's disease. Neurology. 1984; 34: 939-944.

[64] Sotelo JR. Technical improvements in specimen preparation for electron microscopy. Exp. Cell Res. 1957; 13: 599-601.

**109**

*Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target…*

Martínez C, Calatayud M, Morís G, Coto E. Lack of association between protocadherin 11-X/Y (PCDH11X and PCDH11Y) polymorphisms and late onset Alzheimer's disease. Brain Res.

[74] Gabuzda D, Busciglio J, Chen L, Matsudaira P, Yankner B. Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative. J. Biol. Chem. 1994; 269: 13623-13628.

[75] Blass J, Baker A, Ko L, Black, R. Induction of Alzheimer antigens by an uncoupler of oxidative phosphorylation.

Arch. Neurol. 1990; 47: 864-869.

Acad. Sci. 2000; 903: 204-221.

[77] Luo Y, Bond J, Ingram V.

[76] Blass J, Fheu R, Gibson G. Inheritent abnormalities in energy metabolism in Alzheimer disease: Interaction with cerebrovascular compromise. Ann.N.Y.

Compromised mitochondrial function leads to increased cytosolic calcium and to activation of MAP kinases. Proc. Natl. Acad. Sci. USA. 1997; 94: 9705-9710.

[78] Perry G, Roder H, Nunomura A, Takeda A, Friedlich A, Zhu X, Raina A,

Holbrook N, Siedlak S, Harris P, Smith M. Activation of neuronal extracellular receptor kinase (ERK) in Alzheimer disease links oxidative stress

to abnormal phosphorylation. NeuroReport. 1999; 10: 2411-2415.

[79] Zhu X, Rottkamp C, Boux H, Takeda A, Perry G, Smith M. Activation of p38 pathway links tau phosphorylation, oxidative stress and cell cycle related events in Alzheimer disease. J. Neuropathol. Exp. Neurol.

[80] Correia SC, Perry G, Moreira PI.

Alzheimer's disease- pinpointing the roadblocks. Bioch. Biophys. Acta. 2016;

Mitochondrial traffic jams in

2000; 59: 880-888.

1862: 1909-1917.

2011;1383: 252-256.

*DOI: http://dx.doi.org/10.5772/intechopen.98436*

pathology in Alzheimer's disease. Future

[65] Baloyannis SJ. Recent progress of the Golgi technique and electron microscopy to examine dendritic

Neurol. 2013; 8: 239-242.

Demen. 2015; 30: 478-487.

[67] Baloyannis S, Manolidis S,

Disease- A Golgi and Electron Microscope Study. Acta Otolaryngol.

(Stockh) 2000; 120: 247-250.

[69] Baloyannis S, Manolidis S, Manolidis L. The acoustic cortex in Alzheimer's disease. Acta Otolaryngol. (Stockh). 1992; Suppl. 494: 1-13.

[70] Baloyannis SJ, Manolides SL, Manolides LS. Dendritic and spinal pathology in the acoustic cortex in Alzheimer's disease: morphological estimation in Golgi technique and electron microscopy. Acta Otolaryngol.

2002, pp. 1-10.

2011;131: 610-612.

1990; 28: 597-613.

[71] Mesulam M. Large-scale neurocognitive networks and distributed processing for attention, language and memory. Ann. Neurol.

[72] Baloyannis S, Theocharidis T, Manolidis L. Synaptic alterations in the acoustic cortex of the rat following insulin-induced hypoglycemia. Arch Otorhinolaryngol. 1987; 244: 36-43.

[73] Miar A, Alvarez V, Corao AI, Alonso B, Díaz M, Menéndez M,

Manolidis L. Synaptic alterations in the Vestibulocerebellar System in Alzheimer΄s

[68] Baloyannis S. The Golgi apparatus of Purkinje cells in Alzheimer's disease In Jurgen Bohl (Ed) Neuropathology-Back to the roots Shaker Vertag, Aachen,

[66] Baloyannis SJ, Mavroudis I, Mitilineos D, Baloyannis JS, Costa VG. The Hypothalamus in Alzheimer's disease: a Golgi and electron microscope study.Am. J. Alzheimers Dis. Other

*Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target… DOI: http://dx.doi.org/10.5772/intechopen.98436*

[65] Baloyannis SJ. Recent progress of the Golgi technique and electron microscopy to examine dendritic pathology in Alzheimer's disease. Future Neurol. 2013; 8: 239-242.

*Cerebral and Cerebellar Cortex – Interaction and Dynamics in Health and Disease*

[57] Shahpasand K, Uemura I, Saito T, Asano T, Hata K, Shibata K, Hisanaga S. Regulation of mitochondrial transport and inter- microtubule spacing by tau

hyperphosphorylated in Alzheimer's disease. J. Neurosci. 2012; 32:2430-2441.

[58] Baloyannis SJ. Dendritic pathology in Alzheimer's disease. J. Neurol. Sci.

[60] Quintanilla RA, Dolan PJ, Jin YN, Johnson GVW. Truncated tau and Abeta cooperatively impair mitochondria in primary neurons. Neurobiol. Aging.

[61] Baloyannis SJ. Golgi apparatus and protein trafficking in Alzheimer's disease. J. Alzheimers Dis. 2014; 42 (Suppl 3):S153-162. doi: 10.3233/ JAD-132660. PMID: 24946873.

[62] Baloyannis SJ, Mavroudis I, Baloyannis JS, Costa VG. Mammillary Bodies in Alzheimer's Disease: A Golgi and Electron Microscope Study. Am. J. Alzheimers Dis. Other Demen. 2016; 31:

[63] McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of department of health and

human services task force on

Alzheimer's disease. Neurology. 1984;

[64] Sotelo JR. Technical improvements in specimen preparation for electron microscopy. Exp. Cell Res. 1957; 13:

[59] Baloyannis SJ, Mauroudis I, Manolides SL, Manolides LS. Synaptic alterations in the medial geniculate bodies and the inferior colliculi in Alzheimer's disease: a Golgi and electron microscope study. Acta Otolaryngol.

phosphorylation at the sites

2009; 283: 153-157.

2009; 129:416-418.

2012; 33: 619 e25-35.

247-256.

34: 939-944.

599-601.

[49] Correia SC, Moreira PI, Perry G. Unraveling the Role of Mitochondria in Alzheimer's Disease In: Vascular Disease, Alzheimer's Disease, and Mild Cognitive Impairment. Edited by: David J. Libon, Melissa Lamar, Rodney A. Swenson, Kenneth M.

Heilman, Oxford University Press. 2020. DOI: 10.1093/oso/9780190634230.

[50] Ni HM,Williams JA, Ding WX. Mitochondrial dynamics and

mitochondrial quality control. Redox

[51] Bereiter-Hahn J, Vöth M. Dynamic of mitochondria in living cells: shape changes, dislocations, fusion, and fission of mitochondria. Microsc. Res.

[52] Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood C S, et al. Mitochondrial abnormalities in Alzheimer's disease. J. Neurosci. 2001;

Michmizos D. Mitochondrial alterations

Alzheimers Dis. Other Demen. 2004;

[55] Manczak M, Reddy PH. Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons: Implications for mitochondrial dysfunction and neuronal damage. Hum. Mol. Genet. 2012; 21: 2538– 2547.

[56] Lin MY, Sheng ZH. Regulation of mitochondrial transport in neurons. Exper. Cell Res. 2015; 334: 35-44.

[54] Baloyannis SJ, Manolides SL, Manolides LS. Dendritic and spinal pathology in the acoustic cortex in Alzheimer's disease: morphological estimation in Golgi technique and electron microscopy. Acta Otolaryngol.

003.0017.

Biol. 2015; 4; 6-13.

Tech. 1994; 27: 198-219.

[53] Baloyannis SJ, Costa V,

in Alzheimer's disease. Am. J.

21: 3017– 3023.

19: 89-93.

2011; 131: 610-612.

**108**

[66] Baloyannis SJ, Mavroudis I, Mitilineos D, Baloyannis JS, Costa VG. The Hypothalamus in Alzheimer's disease: a Golgi and electron microscope study.Am. J. Alzheimers Dis. Other Demen. 2015; 30: 478-487.

[67] Baloyannis S, Manolidis S, Manolidis L. Synaptic alterations in the Vestibulocerebellar System in Alzheimer΄s Disease- A Golgi and Electron Microscope Study. Acta Otolaryngol. (Stockh) 2000; 120: 247-250.

[68] Baloyannis S. The Golgi apparatus of Purkinje cells in Alzheimer's disease In Jurgen Bohl (Ed) Neuropathology-Back to the roots Shaker Vertag, Aachen, 2002, pp. 1-10.

[69] Baloyannis S, Manolidis S, Manolidis L. The acoustic cortex in Alzheimer's disease. Acta Otolaryngol. (Stockh). 1992; Suppl. 494: 1-13.

[70] Baloyannis SJ, Manolides SL, Manolides LS. Dendritic and spinal pathology in the acoustic cortex in Alzheimer's disease: morphological estimation in Golgi technique and electron microscopy. Acta Otolaryngol. 2011;131: 610-612.

[71] Mesulam M. Large-scale neurocognitive networks and distributed processing for attention, language and memory. Ann. Neurol. 1990; 28: 597-613.

[72] Baloyannis S, Theocharidis T, Manolidis L. Synaptic alterations in the acoustic cortex of the rat following insulin-induced hypoglycemia. Arch Otorhinolaryngol. 1987; 244: 36-43.

[73] Miar A, Alvarez V, Corao AI, Alonso B, Díaz M, Menéndez M,

Martínez C, Calatayud M, Morís G, Coto E. Lack of association between protocadherin 11-X/Y (PCDH11X and PCDH11Y) polymorphisms and late onset Alzheimer's disease. Brain Res. 2011;1383: 252-256.

[74] Gabuzda D, Busciglio J, Chen L, Matsudaira P, Yankner B. Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative. J. Biol. Chem. 1994; 269: 13623-13628.

[75] Blass J, Baker A, Ko L, Black, R. Induction of Alzheimer antigens by an uncoupler of oxidative phosphorylation. Arch. Neurol. 1990; 47: 864-869.

[76] Blass J, Fheu R, Gibson G. Inheritent abnormalities in energy metabolism in Alzheimer disease: Interaction with cerebrovascular compromise. Ann.N.Y. Acad. Sci. 2000; 903: 204-221.

[77] Luo Y, Bond J, Ingram V. Compromised mitochondrial function leads to increased cytosolic calcium and to activation of MAP kinases. Proc. Natl. Acad. Sci. USA. 1997; 94: 9705-9710.

[78] Perry G, Roder H, Nunomura A, Takeda A, Friedlich A, Zhu X, Raina A, Holbrook N, Siedlak S, Harris P, Smith M. Activation of neuronal extracellular receptor kinase (ERK) in Alzheimer disease links oxidative stress to abnormal phosphorylation. NeuroReport. 1999; 10: 2411-2415.

[79] Zhu X, Rottkamp C, Boux H, Takeda A, Perry G, Smith M. Activation of p38 pathway links tau phosphorylation, oxidative stress and cell cycle related events in Alzheimer disease. J. Neuropathol. Exp. Neurol. 2000; 59: 880-888.

[80] Correia SC, Perry G, Moreira PI. Mitochondrial traffic jams in Alzheimer's disease- pinpointing the roadblocks. Bioch. Biophys. Acta. 2016; 1862: 1909-1917.

[81] Lustbader J, Cirilli M, Lin C, Xu H, Takuma K, Wang N, Caspersen C, Chen X, Pollak S, Chaney M, Trinchese F, Liu S, Gunn-Moore F, Lue L, Walker D, Kuppusamy P, Zewier Z, Arancio O, Sten D, Yan S, Wu H. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease. Science. 2004; 304: 448-453.

[82] Benek O, Musílek K, Kuca K. Mitochondrial enzyme ABAD and its role in the development and treatment of Alzheimer's disease. Ceska Slov. Farm. Cas. Ceske Farm. Spolecnosti Slov. Farm. Spolecnosti, 2012; 61: 144-149.

[83] Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, Yan Y, Wang C, Zhang H,Molkentin JD, Gunn-Moore FJ, Vonsattel JP, Arancio O, Chen JX, Yan SD. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease. Nat. Med. 2008; 14: 1097-1105.

[84] Moreira PI, Siedlak SL,Wang X, Santos MS, Oliveira CR, Tabaton M, Nunomura A, Szweda LI, Aliev G, Smith MA, Zhu X, Perry G. Increased autophagic degradation of mitochondria in Alzheimer disease. Autophagy. 2007; 3: 614-615.

[85] Martin-Maestro P, Gargini R, Perry G, Avila J, Garcia-Escudero V. PARK2 enhancement is able to compensate mitophagy alterations found in sporadic Alzheimer's disease. Hum. Mol. 2016; 25: 792-806.

[86] Fang EF, Hou Y, Palikaras K, Adriaanse BA, Kerr JS, Yang B, Lautrup S, Hasan-Olive MM, Caponio D, Dan X, Dan X, Rocktäschel P, Croteau DL, Akbari M, Greig NH, Fladby T, Nilsen H, Cader MZ, Mattson MP, Tavernarakis N, Bohr VA. Mitophagy inhibits amyloidbeta and tau pathology and reverses cognitive deficits in models of

Alzheimer's disease. Nat. Neurosci. 2019; 22: 401-412.

[87] Cummings JL, Morstorf T, Zhong K. Alzheimer's disease drug-development pipeline:few candidates, frequent failures. Alzheimers Res. Ther. 2014; 6: 37.

[88] Takeda A, Loveman E, Clegg A, Kirby J, Picot J, Payne E, Green CA. A systematic review of the clinical effectiveness of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in Alzheimer's disease. Int. J. Geriatr. Psychiatry. 2006; 21: 17-28.

[89] Honig LS, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, Hager K, Andreasen N, Scarpini E, Liu-Seifert H, Case M, Dean RA, Hake A, Sundell K, Poole Hoffmann V, Carlson C, Khanna R, Mintun M, DeMattos R, Selzler KJ, Siemers E. Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease. N. Engl. J. Med. 2018; 378: 321-330.

[90] Wojsiat J, Zoltowska KM, Laskowska- Kaszub K, Wojda U. Oxidant/ antioxidant imbalance in Alzheimer's disease: Therapeutic and diagnostic prospects. Oxid. Med. Cell Longev. 2018; 2018: 6435861.

[91] Kim HS, Suh YH. Minocycline and neurodegenerative diseases. Behav. Brain Res. 2009; 196: 168-179.

[92] Ono K, Naiki H, Yamada M. The development of preventives and therapeutics for Alzheimer's disease thatinhibit the formation of betaamyloid fibrils (fAbeta), as well as destabilize preformed fAbeta. Curr. Pharm. Des. 2006;12: 4357– 4375.

[93] Isopi E, Granzotto A, Corona C, Bomba M, Ciavardelli D, Curcio M, Canzoniero LM, Navarra R, Lattanzio R, Piantelli M, Sensi SL. Pyruvate prevents the development of age-dependent

**111**

439-448.

*Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target…*

Murri L, Rapoport SI, Solaini G. Cytochrome c oxidase and

mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer's disease. Neurobiol. Aging. 2002; 23:

[101] Reddy PH, Manczak M, Yin X, Reddy AP. Synergistic Protective Effects of Mitochondrial Division Inhibitor 1 and Mitochondria- Targeted Small Peptide SS31 in Alzheimer's Disease. J. Alzheim. Dis. 2018; 62: 1549-1565.

[102] Zhang W, Gu GJ, Shen X, Zhang Q, Wang GM, Wang PJ. Neural stem cell transplantation enhances mitochondrial biogenesis in a transgenic mouse model of Alzheimer's disease- like pathology. Neurobiol. Aging, 2015; 36: 1282– 1292.

[103] McManus MJ, Murphy MP,

[104] Lim YA, Grimm A, Giese M, Mensah-Nyagan AG, Villafranca JE, Ittner LM, Eckert A, Götz J. Inhibition of the Mitochondrial Enzyme ABAD Restores the Amyloid-Β-Mediated Deregulation of Estradiol. PloS One,

[105] Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, Yan Y, Wang C, Zhang H, Molkentin JD, Gunn-Moore FJ, Vonsattel JP, Arancio O,

Chen JX, Yan SD. Cyclophilin D

[106] Rubinstein JL, Walker JE, Henderson R. Structure of the

deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease. Nat. Med. 2008; 14:1097-1105.

mitochondrial ATP synthase by electron cryomicroscopy. EMBO J. 2003; 22:

2011; 6: e28887.

6182-6192.

Franklin JL. The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer's disease. J. Neurosci. 2011; 31: 15703-15715.

371-376.

*DOI: http://dx.doi.org/10.5772/intechopen.98436*

cognitive deficits in a mouse model of Alzheimer's disease without reducing amyloid and tau pathology. Neurobiol.

[94] Massey V. The chemical and biological versatility of Riboflavin. Biochem. Soc. Trans. 2000; 28: 283-296.

[95] Bafunno V, Giancaspero TA, Brizio C, Bufano D, Passarella S, Boles E, Barile, M. Riboflavin uptake and FAD synthesis in *Saccharomyces cerevisiae* mitochondria. Involvement of the FLX1p carrier in FAD export. J. Biol.

[96] Johnson JO, Gibbs JR, Megarbane A,

Chem. 2004; 279: 95-102.

2012; 135: 1-8.

Medic. 2017; 6: 52.

Urtizberea JA, Hernandez DG, Foley AR, Arepalli S, Pandraud A, Sanchez JS, Clayton P, Reilly MM, Muntoni F, Abramzon Y, Houlden H, Singleton AB. Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease. Brain,

[97] Udhayabanu T, Manole A, Rajeshwari M, Varalakshmi P,

Houlden H, Ashokkumar B. Riboflavin responsive mitochondrial dysfunction in neurodegenerative diseases. J. Clinic.

[98] Coimbra CG, Junqueira VBC. High doses of riboflavin and the elimination of dietary red meat promote the recovery of some motor functions in Parkinson's disease patients. Braz. J. Med. Biol. Res. 2003; 36: 1409-1417.

[99] Naghashpour M, Amani R,

Samarbafzadeh A, Jafarirad S, Saki Malehi A. Brain-derived neurotrophic and immunologic factors: Beneficial effects of riboflavin on motor disability in murine model of multiple sclerosis. Iran. J. Basic Med. Sci. 2016; 19:

[100] Bosetti F, Brizzi F, Barogi S, Mancuso M, Siciliano G, Tendi EA,

Sarkaki A, Ghadiri A,

Dis. 2015; 81: 214-224.

*Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target… DOI: http://dx.doi.org/10.5772/intechopen.98436*

cognitive deficits in a mouse model of Alzheimer's disease without reducing amyloid and tau pathology. Neurobiol. Dis. 2015; 81: 214-224.

*Cerebral and Cerebellar Cortex – Interaction and Dynamics in Health and Disease*

Alzheimer's disease. Nat. Neurosci.

[87] Cummings JL, Morstorf T, Zhong K. Alzheimer's disease drug-development pipeline:few candidates, frequent failures. Alzheimers Res. Ther.

[88] Takeda A, Loveman E, Clegg A, Kirby J, Picot J, Payne E, Green CA. A systematic review of the clinical

effectiveness of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in Alzheimer's disease. Int. J. Geriatr. Psychiatry. 2006;

[89] Honig LS, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, Hager K, Andreasen N, Scarpini E, Liu-Seifert H, Case M, Dean RA, Hake A, Sundell K,

Solanezumab for Mild Dementia Due to Alzheimer's Disease. N. Engl. J. Med.

Poole Hoffmann V, Carlson C, Khanna R, Mintun M, DeMattos R, Selzler KJ, Siemers E. Trial of

[90] Wojsiat J, Zoltowska KM, Laskowska- Kaszub K, Wojda U. Oxidant/ antioxidant imbalance in Alzheimer's disease: Therapeutic and diagnostic prospects. Oxid. Med. Cell

Longev. 2018; 2018: 6435861.

[91] Kim HS, Suh YH. Minocycline and neurodegenerative diseases. Behav. Brain Res. 2009; 196: 168-179.

[92] Ono K, Naiki H, Yamada M. The development of preventives and therapeutics for Alzheimer's disease thatinhibit the formation of betaamyloid fibrils (fAbeta), as well as destabilize preformed fAbeta. Curr. Pharm. Des. 2006;12: 4357– 4375.

[93] Isopi E, Granzotto A, Corona C, Bomba M, Ciavardelli D, Curcio M, Canzoniero LM, Navarra R, Lattanzio R, Piantelli M, Sensi SL. Pyruvate prevents the development of age-dependent

2018; 378: 321-330.

2019; 22: 401-412.

2014; 6: 37.

21: 17-28.

[81] Lustbader J, Cirilli M, Lin C, Xu H, Takuma K, Wang N, Caspersen C, Chen X, Pollak S, Chaney M, Trinchese F, Liu S, Gunn-Moore F, Lue L, Walker D, Kuppusamy P, Zewier Z, Arancio O, Sten D, Yan S, Wu H. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease. Science. 2004; 304: 448-453.

[82] Benek O, Musílek K, Kuca K. Mitochondrial enzyme ABAD and its role in the development and treatment of Alzheimer's disease. Ceska Slov. Farm. Cas. Ceske Farm. Spolecnosti Slov. Farm. Spolecnosti, 2012; 61:

[83] Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, Yan Y, Wang C, Zhang H,Molkentin JD,

Chen JX, Yan SD. Cyclophilin D

Gunn-Moore FJ, Vonsattel JP, Arancio O,

deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease. Nat. Med. 2008; 14: 1097-1105.

[84] Moreira PI, Siedlak SL,Wang X, Santos MS, Oliveira CR, Tabaton M, Nunomura A, Szweda LI, Aliev G, Smith MA, Zhu X, Perry G. Increased autophagic degradation of mitochondria in Alzheimer disease. Autophagy. 2007;

[85] Martin-Maestro P, Gargini R, Perry G, Avila J, Garcia-Escudero V. PARK2 enhancement is able to compensate mitophagy alterations found in sporadic Alzheimer's disease.

Hum. Mol. 2016; 25: 792-806.

[86] Fang EF, Hou Y, Palikaras K, Adriaanse BA, Kerr JS, Yang B, Lautrup S, Hasan-Olive MM, Caponio D, Dan X, Dan X,

Greig NH, Fladby T, Nilsen H,

Rocktäschel P, Croteau DL, Akbari M,

Cader MZ, Mattson MP, Tavernarakis N, Bohr VA. Mitophagy inhibits amyloidbeta and tau pathology and reverses cognitive deficits in models of

144-149.

3: 614-615.

**110**

[94] Massey V. The chemical and biological versatility of Riboflavin. Biochem. Soc. Trans. 2000; 28: 283-296.

[95] Bafunno V, Giancaspero TA, Brizio C, Bufano D, Passarella S, Boles E, Barile, M. Riboflavin uptake and FAD synthesis in *Saccharomyces cerevisiae* mitochondria. Involvement of the FLX1p carrier in FAD export. J. Biol. Chem. 2004; 279: 95-102.

[96] Johnson JO, Gibbs JR, Megarbane A, Urtizberea JA, Hernandez DG, Foley AR, Arepalli S, Pandraud A, Sanchez JS, Clayton P, Reilly MM, Muntoni F, Abramzon Y, Houlden H, Singleton AB. Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease. Brain, 2012; 135: 1-8.

[97] Udhayabanu T, Manole A, Rajeshwari M, Varalakshmi P, Houlden H, Ashokkumar B. Riboflavin responsive mitochondrial dysfunction in neurodegenerative diseases. J. Clinic. Medic. 2017; 6: 52.

[98] Coimbra CG, Junqueira VBC. High doses of riboflavin and the elimination of dietary red meat promote the recovery of some motor functions in Parkinson's disease patients. Braz. J. Med. Biol. Res. 2003; 36: 1409-1417.

[99] Naghashpour M, Amani R, Sarkaki A, Ghadiri A, Samarbafzadeh A, Jafarirad S, Saki Malehi A. Brain-derived neurotrophic and immunologic factors: Beneficial effects of riboflavin on motor disability in murine model of multiple sclerosis. Iran. J. Basic Med. Sci. 2016; 19: 439-448.

[100] Bosetti F, Brizzi F, Barogi S, Mancuso M, Siciliano G, Tendi EA, Murri L, Rapoport SI, Solaini G. Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer's disease. Neurobiol. Aging. 2002; 23: 371-376.

[101] Reddy PH, Manczak M, Yin X, Reddy AP. Synergistic Protective Effects of Mitochondrial Division Inhibitor 1 and Mitochondria- Targeted Small Peptide SS31 in Alzheimer's Disease. J. Alzheim. Dis. 2018; 62: 1549-1565.

[102] Zhang W, Gu GJ, Shen X, Zhang Q, Wang GM, Wang PJ. Neural stem cell transplantation enhances mitochondrial biogenesis in a transgenic mouse model of Alzheimer's disease- like pathology. Neurobiol. Aging, 2015; 36: 1282– 1292.

[103] McManus MJ, Murphy MP, Franklin JL. The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer's disease. J. Neurosci. 2011; 31: 15703-15715.

[104] Lim YA, Grimm A, Giese M, Mensah-Nyagan AG, Villafranca JE, Ittner LM, Eckert A, Götz J. Inhibition of the Mitochondrial Enzyme ABAD Restores the Amyloid-Β-Mediated Deregulation of Estradiol. PloS One, 2011; 6: e28887.

[105] Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, Yan Y, Wang C, Zhang H, Molkentin JD, Gunn-Moore FJ, Vonsattel JP, Arancio O, Chen JX, Yan SD. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease. Nat. Med. 2008; 14:1097-1105.

[106] Rubinstein JL, Walker JE, Henderson R. Structure of the mitochondrial ATP synthase by electron cryomicroscopy. EMBO J. 2003; 22: 6182-6192.

[107] Beck SJ, Guo L, Phensy A, Tian J, Wang L, Tandon N, Gauba E, Lu L, Pascual JM, Kroener S, Du H. Deregulation of mitochondrial F1FO-ATP synthase via OSCP in Alzheimer's disease. Nat. Commun. 2016; 7: 11483.

[108] Monteiro-Cardoso VF, Oliveira MM, Melo T, Domingues MR, Moreira PI, Ferreiro E, Peixoto F, Videira RA. Cardiolipin profile changes are associated to the early synaptic mitochondrial dysfunction in Alzheimer's disease. J. Alzheimer's Dis. 2015; 43: 1375-1392.

[109] Romani M. Enhancing mitochondrial quality control to fight neuromuscular degeneration in aging and disease. Thesis, Lausanne EPFL, 2021.

[110] Gupta VK, Scheunemann L, Eisenberg T, Mertel S, Bhukel A, Koemans TS, Kramer JM, Liu KS, Schroeder S, Stunnenberg HG, Sinner F, Magnes C, Pieber TR, Dipt S, Fiala A, Schenck A, Schwaerzel M, Madeo F, Sigrist SJ. Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner. Nat. Neurosci. 2013; 16:1453-1460.

[111] Turunc Bayrakdar E, Uyanikgil Y, Kanit L, Koylu E, Yalcin A. Nicotinamide treatment reduces the levels of oxidative stress, apoptosis, and PARP-1 activity in Abeta(1-42)-induced rat model of Alzheimer's disease. Free Radic. Res. 2014; 48:146-158.

[112] Geisler JG, Marosi K, Halpern J, Mattson MP. DNP, mitochondrial uncoupling, and neuroprotection: A little dab'll do ya. Alzheimers Dement. 2017; 13: 582-591.

[113] Qian C, Yu YJ. Mitophagy in Alzheimer's Disease and Other Age-Related Neurodegenerative Diseases Cells. 2020; 9: 150; doi: 10.3390 /cells 9010150.

[114] Lipinski MM, Zheng B, Lu T, Yan ZY, Py BF, Ng A, Xavier RJ, Li C, Yankner BA, Scherzer CR, Yuan JY. Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease. Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 14164-14169.

[115] Dusetti NJ, Jiang Y, Vaccaro MI, Tomasini R, Azizi Samir A, Calvo EL, Ropolo A, Fiedler F, Mallo GV, Dagorn JC, Iovanna JL. Cloning and expression of the rat vacuole membrane protein 1 (VMP1), a new gene activated in pancreas with acute pancreatitis, which promotes vacuole formation. Biochem. Biophys. Res. Commun. 2002; 290;641-649.

[116] Wang P, Xi Chen Y, Wang CJ, Liu X, Wang Y, Wu H, Cai H, Han-Ming Shen Le W. Essential role for autophagy protein VMP1 in maintaining neuronal homeostasis and preventing axonal degeneration. Cell Death and Disease. 2021; 12:116-130.

[117] Komatsu M, Wang QJ, Holstein GR, Friedrich VL Jr, Iwata J, Kominami E, Chait BT, Tanaka K, Yue Z. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc. Natl. Acad. Sci. USA. 2007; 104: 14489-14494.

[118] Brines M, Cerami A. Emerging biological roles for erythropoietin in the nervous system. Nat. Rev. Neurosci. 2005; 6: 484-494.

[119] Jang W, Park J, Shin KJ, Kim JS, Youn J, Cho JW, Oh E, Ahn JY, Oh KW, Kim HT. Safety and efficacy of recombinant human erythropoietin treatment of non-motor symptoms in Parkinson's disease. J. Neurol. Sci. 2014; 337: 47-54.

[120] Rey F, Ottolenghi S, Giallongo T, Balsari A, Martinelli C, Rey R, Allevi R,

**113**

*Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target…*

[128] Sheu SS, Nauduri D, Anders MW. Targeting antioxidants to mitochondria: a new therapeutic direction. Biochim. Biophys. Acta, 2006; 1762: 256-265.

[129] Zhao K, Zhao GM, Wu D, Soong Y, Birk AV, Schiller PW, Szeto HH. Cellpermeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. J. Biol. Chem. 2004; 279:

[130] Hemachandra RP, Manczak M, Kandimalla R. Mitochondria-targeted small molecule SS31: a potential candidate for the treatment of Alzheimer's disease. Hum. Mo. Gen.

[131] Calkins MJ, Manczak M, Reddy PH. Mitochondria-targeted antioxidant SS31

[132] Li PA, Hou X, Hao S. Mitochondrial biogenesis in neurodegeneration. J. Neurosci. Res. 2017; 95: 2025-2029.

[133] Sheng B, Wang X, Su B, Lee HG, Casadesus G, Perry G, Zhu X. Impaired mitochondrial biogenesis contributes to

[134] Uittenbogaard M, Chiaramello A. Mitochondrial biogenesis: A therapeutic target for neurodevelopmental disorders and neurodegenerative diseases. Curr. Pharm. Des. 2014; 20: 5574-5593.

[135] Gong B, Pan Y, Vempati P, Zhao W, Knable L, Ho L, Wang J, Sastre M, Ono K, Sauve AA, Pasinetti GM. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ

mitochondrial dysfunction in Alzheimer's disease. J. Neurochem.

2012; 120: 419-429.

prevents amyloid beta-induced mitochondrial abnormalities and synaptic degeneration in Alzheimer's disease. Pharmaceuticals (Basel), 2012;

34682-34690.

2017; 26: 1483-1496.

5: 1103-1119.

*DOI: http://dx.doi.org/10.5772/intechopen.98436*

Mazzucchelli S, Foresti R, Samaja M, Carelli S. Mitochondrial Metabolism as Target of the Neuroprotective Role of

Giulio AMD, Zuccotti GV,

Erythropoietin in Parkinson's Disease. Antioxidants (Basel).

[121] Copeland DE, Dalton AJ. An association between mitochondria and the endoplasmic reticulum in cells of the pseudobranch gland of a teleost. J. Biophys. Biochem. Cytol. 1959; 5:

[122] Bereiter-Hahn J. Behavior of mitochondria in the living cell. Int. Rev.

[123] Area-Gomez E, de Groof AJ, Boldogh I, Bird TD, Gibson GE, Koehler CM, Yu WH, Duff KE, Yaffe MP, Pon LA, Schon EA.

Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria. Am. J. Pathol. 2009; 175:

[124] Weiwei Y, Haiqiang J, Yining H. Mitochondria-associated membranes (MAMs): a potential therapeutic target for treating Alzheimer's disease. Clinical

[125] García-Pérez C, Hajnóczky G, Csordás G. Physical coupling supports the local Ca2+ transfer between

[126] Wang X, Zheng W. Ca2+ homeostasis dysregulation in

1101/ cshperspect. a013235.

2019; 33: 6697-6712.

sarcoplasmic reticulum subdomains and the mitochondria in heart muscle. J. Biol. Chem. 2008; 283: 32771-32780.

Alzheimer's disease: a focus on plasma membrane and cell organelles. FASEB J.

[127] Flis VV, Daum G. Lipid transport between the endoplasmic reticulum and mitochondria. Cold Spring Harb, Perspect, Biol. 2013; 5: a013235 doi: 10.

Science. 2021; 135: 109-126.

Cytol. 1990; 122: 1-63.

2021;10:121.

393-396.

1810-1816.

*Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target… DOI: http://dx.doi.org/10.5772/intechopen.98436*

Giulio AMD, Zuccotti GV, Mazzucchelli S, Foresti R, Samaja M, Carelli S. Mitochondrial Metabolism as Target of the Neuroprotective Role of Erythropoietin in Parkinson's Disease. Antioxidants (Basel). 2021;10:121.

*Cerebral and Cerebellar Cortex – Interaction and Dynamics in Health and Disease*

[114] Lipinski MM, Zheng B, Lu T, Yan ZY, Py BF, Ng A, Xavier RJ, Li C, Yankner BA, Scherzer CR, Yuan JY. Genome-wide analysis reveals

mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease. Proc. Natl. Acad. Sci. U.S.A.

[115] Dusetti NJ, Jiang Y, Vaccaro MI, Tomasini R, Azizi Samir A, Calvo EL, Ropolo A, Fiedler F, Mallo GV, Dagorn JC, Iovanna JL. Cloning and expression of the rat vacuole membrane protein 1 (VMP1), a new gene activated in pancreas with acute pancreatitis, which promotes vacuole formation. Biochem. Biophys. Res. Commun. 2002;

[116] Wang P, Xi Chen Y, Wang CJ, Liu X, Wang Y, Wu H, Cai H, Han-Ming Shen Le W. Essential role for autophagy protein VMP1 in maintaining neuronal homeostasis and preventing axonal degeneration. Cell Death and Disease.

[117] Komatsu M, Wang QJ, Holstein GR, Friedrich VL Jr, Iwata J, Kominami E, Chait BT, Tanaka K, Yue Z. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc. Natl. Acad. Sci. USA. 2007; 104:

[118] Brines M, Cerami A. Emerging biological roles for erythropoietin in the nervous system. Nat. Rev. Neurosci.

[119] Jang W, Park J, Shin KJ, Kim JS, Youn J, Cho JW, Oh E, Ahn JY, Oh KW,

[120] Rey F, Ottolenghi S, Giallongo T, Balsari A, Martinelli C, Rey R, Allevi R,

Kim HT. Safety and efficacy of recombinant human erythropoietin treatment of non-motor symptoms in Parkinson's disease. J. Neurol. Sci. 2014;

2010; 107: 14164-14169.

290;641-649.

2021; 12:116-130.

14489-14494.

2005; 6: 484-494.

337: 47-54.

[107] Beck SJ, Guo L, Phensy A, Tian J, Wang L, Tandon N, Gauba E, Lu L, Pascual JM, Kroener S, Du H.

Deregulation of mitochondrial F1FO-ATP synthase via OSCP in Alzheimer's disease. Nat. Commun. 2016; 7: 11483.

Oliveira MM, Melo T, Domingues MR, Moreira PI, Ferreiro E, Peixoto F, Videira RA. Cardiolipin profile changes are associated to the early synaptic mitochondrial dysfunction in

Alzheimer's disease. J. Alzheimer's Dis.

mitochondrial quality control to fight neuromuscular degeneration in aging

[110] Gupta VK, Scheunemann L, Eisenberg T, Mertel S, Bhukel A, Koemans TS, Kramer JM, Liu KS, Schroeder S, Stunnenberg HG, Sinner F, Magnes C, Pieber TR, Dipt S, Fiala A, Schenck A, Schwaerzel M, Madeo F, Sigrist SJ. Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner. Nat. Neurosci. 2013; 16:1453-1460.

[111] Turunc Bayrakdar E, Uyanikgil Y,

Nicotinamide treatment reduces the levels of oxidative stress, apoptosis, and PARP-1 activity in Abeta(1-42)-induced rat model of Alzheimer's disease. Free

[112] Geisler JG, Marosi K, Halpern J, Mattson MP. DNP, mitochondrial uncoupling, and neuroprotection: A little dab'll do ya. Alzheimers Dement.

[113] Qian C, Yu YJ. Mitophagy in Alzheimer's Disease and Other Age-Related Neurodegenerative Diseases Cells. 2020; 9: 150; doi: 10.3390 /cells

Kanit L, Koylu E, Yalcin A.

Radic. Res. 2014; 48:146-158.

2017; 13: 582-591.

[108] Monteiro-Cardoso VF,

[109] Romani M. Enhancing

2015; 43: 1375-1392.

and disease. Thesis, Lausanne EPFL, 2021.

**112**

9010150.

[121] Copeland DE, Dalton AJ. An association between mitochondria and the endoplasmic reticulum in cells of the pseudobranch gland of a teleost. J. Biophys. Biochem. Cytol. 1959; 5: 393-396.

[122] Bereiter-Hahn J. Behavior of mitochondria in the living cell. Int. Rev. Cytol. 1990; 122: 1-63.

[123] Area-Gomez E, de Groof AJ, Boldogh I, Bird TD, Gibson GE, Koehler CM, Yu WH, Duff KE, Yaffe MP, Pon LA, Schon EA. Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria. Am. J. Pathol. 2009; 175: 1810-1816.

[124] Weiwei Y, Haiqiang J, Yining H. Mitochondria-associated membranes (MAMs): a potential therapeutic target for treating Alzheimer's disease. Clinical Science. 2021; 135: 109-126.

[125] García-Pérez C, Hajnóczky G, Csordás G. Physical coupling supports the local Ca2+ transfer between sarcoplasmic reticulum subdomains and the mitochondria in heart muscle. J. Biol. Chem. 2008; 283: 32771-32780.

[126] Wang X, Zheng W. Ca2+ homeostasis dysregulation in Alzheimer's disease: a focus on plasma membrane and cell organelles. FASEB J. 2019; 33: 6697-6712.

[127] Flis VV, Daum G. Lipid transport between the endoplasmic reticulum and mitochondria. Cold Spring Harb, Perspect, Biol. 2013; 5: a013235 doi: 10. 1101/ cshperspect. a013235.

[128] Sheu SS, Nauduri D, Anders MW. Targeting antioxidants to mitochondria: a new therapeutic direction. Biochim. Biophys. Acta, 2006; 1762: 256-265.

[129] Zhao K, Zhao GM, Wu D, Soong Y, Birk AV, Schiller PW, Szeto HH. Cellpermeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. J. Biol. Chem. 2004; 279: 34682-34690.

[130] Hemachandra RP, Manczak M, Kandimalla R. Mitochondria-targeted small molecule SS31: a potential candidate for the treatment of Alzheimer's disease. Hum. Mo. Gen. 2017; 26: 1483-1496.

[131] Calkins MJ, Manczak M, Reddy PH. Mitochondria-targeted antioxidant SS31 prevents amyloid beta-induced mitochondrial abnormalities and synaptic degeneration in Alzheimer's disease. Pharmaceuticals (Basel), 2012; 5: 1103-1119.

[132] Li PA, Hou X, Hao S. Mitochondrial biogenesis in neurodegeneration. J. Neurosci. Res. 2017; 95: 2025-2029.

[133] Sheng B, Wang X, Su B, Lee HG, Casadesus G, Perry G, Zhu X. Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer's disease. J. Neurochem. 2012; 120: 419-429.

[134] Uittenbogaard M, Chiaramello A. Mitochondrial biogenesis: A therapeutic target for neurodevelopmental disorders and neurodegenerative diseases. Curr. Pharm. Des. 2014; 20: 5574-5593.

[135] Gong B, Pan Y, Vempati P, Zhao W, Knable L, Ho L, Wang J, Sastre M, Ono K, Sauve AA, Pasinetti GM. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ

coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models. Neurobiol. Aging. 2013; 34: 1581-1588.

[136] Reddy PH, Manczak M, Yin X, Grady MC, Mitchell A, Kandimalla R, Kuruva CS. Protective effects of a natural product, curcumin, against amyloid β induced mitochondrial and synaptic toxicities in Alzheimer's disease. J. Investig. Med. 2016; 64: 1220-1234.

[137] Heneka MT, Fink A, Doblhammer G. Effect of pioglitazone medication on the incidence of dementia. Ann. Neurol. 2015; 78: 284-294.

[138] Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, Asthana S, Fishel MA, Kulstad JJ, Green PS, Cook DG, Kahn SE, Keeling ML, Craft S. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am. J. Geriatr. Psychiatry. 2005; 13: 950-958.

[139] Wang CF, Song CY, Wang X, Huang LY, Ding M, Yang H, Wang P, Xu LL, Xie ZH, Bi JZ. Protective effects of melatonin on mitochondrial biogenesis and mitochondrial structure and function in the HEK293-APPswe cell model of Alzheimer's disease. Eur. Rev. Med. Pharmacol. Sci. 2019; 23: 3542-3550.

[140] Shukla M, Govitrapong P, Boontem P, Reiter RJ, Satayavivad J. Mechanisms of Melatonin in Alleviating Alzheimer ' s Disease. Curr. Neuropharmacol. 2017;15:1010-1031.

[141] Espino J, Bejarano I, Redondo PC, Rosado JA, Barriga C, Reiter RJ, Pariente JA, Rodríguez AB. Melatonin

reduces apoptosis induced by calcium signaling in human leukocytes: Evidence for the involvement of mitochondria and Bax activation. J. Membr. Biol. 2010; 233:105-118.

[142] Mladinov M, Yeop Oh J, Petersen C, Eser R, Hua Li S, Theofilas P, Spina S, Seeley WW, Bittencourt JC, Neylan TC, Grinberg LT. Specific pattern of melanin-concentrating hormone (MCH) neuron degeneration in Alzheimer's disease and possible clinical implications medRxiv 2021;01.27.21250608; doi: https: //doi. org/ 10.1101 /2021. 01. 27.21250608

[143] Hashemi M, Ghavami S, Eshraghi M, Booy EP, Los M. Cytotoxic effects of intra and extracellular zinc chelation on human breast cancer cells. Eur. J. Pharmacol. 2007; 557 : 9-19.

[144] de la Torre JC, Mussivand T. Can disturbed brain microcirculation cause Alzheimer's disease? Neurol. Res. 1993; 15: 146-153.

[145] Zhao Y, Gong CX. From chronic cerebral hypoperfusion to Alzheimerlike brain pathology and neurodegeneration. Cell Mol. Neurobiol. 2015; 35: 101-110.

[146] Govindpani K, McNamara LG, Smith NR, Vinnakota C, Waldvogel HJ, Faull RL, Kwakowsky A. Vascular dysfunction in Alzheimer's disease: A prelude to the pathological process or a consequence of it? J. Clin. Med. 2019; 8: 651.

[147] de la Torre JC. Deciphering Alzheimer's Disease Pathogenic Pathway: Role of Chronic Brain Hypoperfusion on p-Tau and mTOR. J. Alzheimers Dis. 2021; 79: 1381-1396.

[148] MacAskill AF, Kittler JT. Control of mitochondrial transport and localization in neurons. Trends Cell Biol. 2010; 20: 102-112.

**115**

*Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target…*

*DOI: http://dx.doi.org/10.5772/intechopen.98436*

Arumugam TV, Phan TG, Srikanth VK,

impairment and Alzheimer's disease: Role of cerebral hypoperfusion and oxidative stress. Naunyn Schmiedebergs Arch. Pharmacol. 2012; 385: 953-959.

[150] Marco M, Shaw PJ, Ferraiuolo L, Blackburn DJ, Venneri A, Mortiboys H.

Alzheimer's Disease: A Biomarker of the Future? Biomedicines 2021; 9: 63.

Mitochondrial Dysfunction in

https://doi.org/10.3390/ biomedicines9010063

[149] Kim HA, Miller AA, Drummond GR, Thrift AG,

Sobey CG. Vascular cognitive

*Mitochondria in the Cerebral and Cerebellar Cortex in Alzheimer's Disease, Target… DOI: http://dx.doi.org/10.5772/intechopen.98436*

[149] Kim HA, Miller AA, Drummond GR, Thrift AG, Arumugam TV, Phan TG, Srikanth VK, Sobey CG. Vascular cognitive impairment and Alzheimer's disease: Role of cerebral hypoperfusion and oxidative stress. Naunyn Schmiedebergs Arch. Pharmacol. 2012; 385: 953-959.

*Cerebral and Cerebellar Cortex – Interaction and Dynamics in Health and Disease*

reduces apoptosis induced by calcium signaling in human leukocytes: Evidence for the involvement of mitochondria and Bax activation. J. Membr. Biol. 2010; 233:105-118.

[142] Mladinov M, Yeop Oh J, Petersen C, Eser R, Hua Li S, Theofilas P, Spina S, Seeley WW, Bittencourt JC, Neylan TC,

Alzheimer's disease and possible clinical

2021;01.27.21250608; doi: https: //doi. org/ 10.1101 /2021. 01. 27.21250608

Eshraghi M, Booy EP, Los M. Cytotoxic effects of intra and extracellular zinc chelation on human breast cancer cells. Eur. J. Pharmacol. 2007; 557 : 9-19.

[144] de la Torre JC, Mussivand T. Can disturbed brain microcirculation cause Alzheimer's disease? Neurol. Res. 1993;

[145] Zhao Y, Gong CX. From chronic cerebral hypoperfusion to Alzheimer-

[146] Govindpani K, McNamara LG, Smith NR, Vinnakota C, Waldvogel HJ, Faull RL, Kwakowsky A. Vascular dysfunction in Alzheimer's disease: A prelude to the pathological process or a

consequence of it? J. Clin. Med.

[147] de la Torre JC. Deciphering Alzheimer's Disease Pathogenic Pathway: Role of Chronic Brain Hypoperfusion on p-Tau and mTOR. J. Alzheimers Dis. 2021; 79: 1381-1396.

mitochondrial transport and

2010; 20: 102-112.

[148] MacAskill AF, Kittler JT. Control of

localization in neurons. Trends Cell Biol.

neurodegeneration. Cell Mol. Neurobiol.

like brain pathology and

2015; 35: 101-110.

2019; 8: 651.

Grinberg LT. Specific pattern of melanin-concentrating hormone (MCH) neuron degeneration in

[143] Hashemi M, Ghavami S,

implications medRxiv

15: 146-153.

coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models. Neurobiol. Aging. 2013; 34:

[136] Reddy PH, Manczak M, Yin X, Grady MC, Mitchell A, Kandimalla R, Kuruva CS. Protective effects of a natural product, curcumin, against amyloid β induced mitochondrial and synaptic toxicities in Alzheimer's disease. J. Investig. Med. 2016; 64:

Doblhammer G. Effect of pioglitazone

1581-1588.

1220-1234.

284-294.

950-958.

3542-3550.

[137] Heneka MT, Fink A,

medication on the incidence of dementia. Ann. Neurol. 2015; 78:

[138] Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, Asthana S, Fishel MA, Kulstad JJ, Green PS, Cook DG, Kahn SE, Keeling ML, Craft S. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am. J. Geriatr. Psychiatry. 2005; 13:

[139] Wang CF, Song CY, Wang X, Huang LY, Ding M, Yang H, Wang P, Xu LL, Xie ZH, Bi JZ. Protective effects

of melatonin on mitochondrial

[140] Shukla M, Govitrapong P, Boontem P, Reiter RJ, Satayavivad J. Mechanisms of Melatonin in Alleviating

Alzheimer ' s Disease. Curr.

Neuropharmacol. 2017;15:1010-1031.

[141] Espino J, Bejarano I, Redondo PC, Rosado JA, Barriga C, Reiter RJ, Pariente JA, Rodríguez AB. Melatonin

biogenesis and mitochondrial structure and function in the HEK293-APPswe cell model of Alzheimer's disease. Eur. Rev. Med. Pharmacol. Sci. 2019; 23:

**114**

[150] Marco M, Shaw PJ, Ferraiuolo L, Blackburn DJ, Venneri A, Mortiboys H. Mitochondrial Dysfunction in Alzheimer's Disease: A Biomarker of the Future? Biomedicines 2021; 9: 63. https://doi.org/10.3390/ biomedicines9010063

**117**

**Chapter 6**

Output

**Abstract**

*Kenneth J. McLeod*

second heart, soleus muscle stimulation

soon dominant healthcare costs in many countries.

**1. Introduction**

Reversal of Cognitive Aging

through Enhancement of Cardiac

Cognitive aging is a progressive condition leading to dementia, a condition which is now the sixth leading cause of death in the U.S., as well as being among the most expensive healthcare conditions to manage. With over 5 million affected in the U.S. alone, the annual costs to the Medicare/Medicaid system exceeds \$200 billion, and with the rising age of the population, annual costs of dementia care are expected to exceed \$500 billion by 2040. As there is no cure for dementia, a consensus has formed that a more pragmatic goal of research should be developing interventions capable of slowing or preventing cognitive aging. We propose that this is a readily achievable goal. Cognitive impairment is closely linked to cerebral perfusion, and cerebral perfusion is a function of cardiac output. In turn, cardiac output is completely dependent on venous return, which in the upright human, relies on adequate soleus muscle activity. As modern adults rarely squat, which is necessary for maintaining the soleus muscle, soleus insufficiency develops early in adulthood in most people. However, soleus muscle insufficiency can be reversed, resulting in improved cardiac output, cerebral perfusion, and the prevention of cognitive aging.

**Keywords:** dementia prevention, cerebral perfusion, cardiac output, venous return,

Dementia is a major cause of morbidity and mortality in the developed world. Dementia, in all of its forms, is a progressive condition, with an incidence of less than 5% through age 79, but reaching 40% for those over age 90 [1]. Given the aging demographics of the developed world, the economic impact of this condition could

There is currently no cure for dementia, and numerous pharmaceutical firms have abandoned the search for a cure. In particular, interventions based on the beta-amyloid hypothesis which has guided dementia drug therapy development for the last three decades has come under increasing scrutiny as drugs which effectively reduce beta-amyloid accumulation appear to exacerbate, rather than ameliorate, the symptoms associated with dementia [2]. It is therefore incumbent that we take a fresh approach to understanding dementia, in particular, we suggest it is important to develop a more thorough understanding of the numerous physiologic interactions associated with progression of cognitive impairment with age. Such understanding

## **Chapter 6**
