**1. Introduction**

Alzheimer's disease (AD) is one of the most enigmatic and multidimensional neurodegenerative diseases of the brain. The high incidence in aging, the ongoing number of the patients and the social, humanitarian and economic impact of the disease [1], as well as the irreversible course of the disease, the failure of therapeutic interventions [2] and the fatal outcome impose on the neuroscientists and the society a combined attempt for the amelioration of the quality of life of the patients at least by the reduction of risk factors in the initial stages of the disease [3].

The clinical manifestation of Alzheimer's disease, starting from the inability to encode new memories, includes progressive and irreversible cognitive decline, affecting memory and judgment, loss of professional skills and verbal capacities, impairment of learning new informations and gradual disarrangement of the social behavior [4, 5] resulting in isolation of the patient in the framework of an obvious functional incapacity, encountering in vegetative state eventually.

The neuropathological background of AD mostly consists of selective neuronal loss [6, 7], substantial morphological and morphometric alterations of the synapses [8–11], marked mitochondrial alterations, even in the initial stages of the disease [12, 13], tau pathology [14] resulting in the formation of neurofibrillary tangles (NFT) by the accumulation of hyperphosphorylated tau protein [15], many inflammatory phenomena, alterations of brain capillaries [16] and various extensive extracellular deposits of Aβ peptide's polymers, in the form of polymorphic neuritic plaques, [17, 18].

Pathological alterations of the organelles in the soma, the axons, the dendrites and the synapses of neurons are observed in electron microscopy, even in the initial stage of the disease [19] in areas with minimal typical Alzheimer's pathology, namely aggregations of Aβ peptide and neurofibrillary tangles. The majority of the alterations of the organelles in Alzheimer's disease particularly concern the Golgi complex [19], the microtubules, the synaptic vesicles and mostly the mitochondria [20–22].

The etiopathology of the sporadic cases of Alzheimer's disease remains a real problem in spite of the multidimensional extensive ongoing research in the last decades [23, 24] on the crucial fields of genetics [25, 26], molecular biology [27, 28], neuropathology [29, 30], neuroimmunology [31, 32], pathophysiology [33], neuroimaging [34] and neurochemistry [35–38].

The pathogenetic mechanisms embrace a diverse range of hypotheses which attempt to decipher the real cause of memory and reasoning decline in AD. Among the many hypothesis, the most mattering are (a) the amyloid hypothesis [39, 40], (b) the metabolic and synaptic dysfunction hypothesis [41], (c) the hypothesis of translational neurodegeneration [42], (d) the tau hypothesis [43], (e) the hypothesis of neuroinflammation [44], (f) the cholinergic hypothesis [45], (g) the oxidative stress [46], (h) the vascular hypothesis [47, 48], (i) the glucose hypometabolism hypothesis [49], (j) the autoimmune hypothesis [50], (k) the endocrine hypothesis [51, 52], (l) the mitochondrial dysfunction [53, 54] and (m) the Golgi complex hypothesis [55–57].

Many of those hypotheses are basely interrelated, such as the amyloid hypothesis and the oxidative stress ones [58, 59], the amyloid and the tau hypothesis [60], the oxidative stress and the mitochondrial dysfunction [61], the mitochondrial dysfunction, energy deficiency and oxidative stress [61, 62], the mitochondria dysfunction and the synaptic pathology [22, 63], the tau pathology and the vascular hypothesis [64], the cholinergic dysfunction and the amyloid hypothesis [65], amyloid, tau and neurodegeneration hypothesis [66], the mitochondria and the dendritic hypothesis [67–69] and the immune reactions, microglia, tau, Aβ peptide, lipid processing and neurodegeneration hypothesis [70–73].

Mitochondria hypothesis advocates in favor of the important role that mitochondrial dysfunction may play in the early stages of Alzheimer's disease [21] by inducing energy deficiency and oxidative stress [22], which would be associated with β-amyloid (Aβ) neurotoxicity. It is well known that mitochondria, which has been defined as organelles in tissue culture since 1914 [74] are normally involved in aging

**37**

*Mitochondria and Alzheimer's Disease: An Electron Microscopy Study*

process [75–77], since mitochondrial function declines as the age advances, resulting in decrease of ATP production and increase of free oxygen radicals formation, given that ATP synthase is located in the inner mitochondrial membrane, playing a

In addition, morphological alterations of mitochondria, resulting in deficiency of mitochondrial electron transport proteins, with considerable consequences upon the energy supply of nerve cells have been described in Alzheimer's disease and other degenerative conditions of the brain [12, 21, 78, 79], which are also associated

It is also particularly noticeable that morphological abnormalities of mitochondria are seen in neurons lacking neurofibrillary tangles [12] suggesting that mitochondrial degeneration might be among the earliest signs of Alzheimer's

The fact that maternal influence seems to be a risk factor for Alzheimer's disease morbidity, according to epidemiologic studies [81, 82], and to combined neuropsychological and neuroimaging investigations [83] plead in favor of the substantial role that mitochondria may also play in the pathogenetic cascade of Alzheimer's

In this perspective article, we attempted to describe the ultrastructural alterations of mitochondria in various neocortical and subcortical areas of the brain of

This electron microscope study is based on examination of 25 brains obtained at autopsy 2–7 hours after death at a room temperature of 40°C. All of the brains were derived from patients aged 55–80 years, who have had a history of dementia, which

The patients fulfilled on repeated clinical examinations and assessments all the psychological, psychiatric and neurological criteria of AD [84–86]. The patients have had 18 years of education, and had a fluency in their native language, two of them being also bilingual with equal fluency in both of the languages. The usual diagnostic assessment was based on the medical history, the physical examination, including cardiological investigation, neurological examination, psychiatric evalua-

The cognition of the patients was evaluated by battery of neuropsychological testing [87], including mini mental state examination (MMSE) [88, 89], dementia rating scale (DRS) [90, 91], ADAS-COX test [92, 93] and the brief memory execu-

All the patients underwent an EEG examination and a carotid examination by duplex Doppler. Neuroimaging was performed including computerized tomography (CT), magnetic resonance imaging (MRI) of the brain and a single-photon emission computed tomography (SPECT) [95]. All the methods of clinical and laboratory investigations were evocative for Alzheimer's disease. The patients passed away due

In addition, we dissected and examined in electron microscopy 25 brains, which were unremarkable from the neuropathological point of view, derived from apparently healthy individuals of the same age range with the AD patients, using them as

patients who suffered from Alzheimer's disease at the early stages.

was definitely diagnosed 1 or 3 years prior to the end of their life.

tion and detailed neuropsychological testing.

*DOI: http://dx.doi.org/10.5772/intechopen.84881*

key role in the energy homeostasis of the cell.

with oxidative stress [80].

morphological alterations.

**2. Material and methods**

tive test (BMET) [94].

to heart arrest.

normal controls.

disease.

**2.1 Material**

*Mitochondria and Alzheimer's Disease: An Electron Microscopy Study DOI: http://dx.doi.org/10.5772/intechopen.84881*

process [75–77], since mitochondrial function declines as the age advances, resulting in decrease of ATP production and increase of free oxygen radicals formation, given that ATP synthase is located in the inner mitochondrial membrane, playing a key role in the energy homeostasis of the cell.

In addition, morphological alterations of mitochondria, resulting in deficiency of mitochondrial electron transport proteins, with considerable consequences upon the energy supply of nerve cells have been described in Alzheimer's disease and other degenerative conditions of the brain [12, 21, 78, 79], which are also associated with oxidative stress [80].

It is also particularly noticeable that morphological abnormalities of mitochondria are seen in neurons lacking neurofibrillary tangles [12] suggesting that mitochondrial degeneration might be among the earliest signs of Alzheimer's morphological alterations.

The fact that maternal influence seems to be a risk factor for Alzheimer's disease morbidity, according to epidemiologic studies [81, 82], and to combined neuropsychological and neuroimaging investigations [83] plead in favor of the substantial role that mitochondria may also play in the pathogenetic cascade of Alzheimer's disease.

In this perspective article, we attempted to describe the ultrastructural alterations of mitochondria in various neocortical and subcortical areas of the brain of patients who suffered from Alzheimer's disease at the early stages.

## **2. Material and methods**

#### **2.1 Material**

*Redirecting Alzheimer Strategy - Tracing Memory Loss to Self Pathology*

eventually.

plaques, [17, 18].

mitochondria [20–22].

complex hypothesis [55–57].

hypothesis [70–73].

neuroimaging [34] and neurochemistry [35–38].

The clinical manifestation of Alzheimer's disease, starting from the inability to encode new memories, includes progressive and irreversible cognitive decline, affecting memory and judgment, loss of professional skills and verbal capacities, impairment of learning new informations and gradual disarrangement of the social behavior [4, 5] resulting in isolation of the patient in the framework of an obvious functional incapacity, encountering in vegetative state

The neuropathological background of AD mostly consists of selective neuronal loss [6, 7], substantial morphological and morphometric alterations of the synapses [8–11], marked mitochondrial alterations, even in the initial stages of the disease [12, 13], tau pathology [14] resulting in the formation of neurofibrillary tangles (NFT) by the accumulation of hyperphosphorylated tau protein [15], many inflammatory phenomena, alterations of brain capillaries [16] and various extensive extracellular deposits of Aβ peptide's polymers, in the form of polymorphic neuritic

Pathological alterations of the organelles in the soma, the axons, the dendrites

The etiopathology of the sporadic cases of Alzheimer's disease remains a real problem in spite of the multidimensional extensive ongoing research in the last decades [23, 24] on the crucial fields of genetics [25, 26], molecular biology [27, 28], neuropathology [29, 30], neuroimmunology [31, 32], pathophysiology [33],

The pathogenetic mechanisms embrace a diverse range of hypotheses which attempt to decipher the real cause of memory and reasoning decline in AD. Among the many hypothesis, the most mattering are (a) the amyloid hypothesis [39, 40], (b) the metabolic and synaptic dysfunction hypothesis [41], (c) the hypothesis of translational neurodegeneration [42], (d) the tau hypothesis [43], (e) the hypothesis of neuroinflammation [44], (f) the cholinergic hypothesis [45], (g) the oxidative stress [46], (h) the vascular hypothesis [47, 48], (i) the glucose hypometabolism hypothesis [49], (j) the autoimmune hypothesis [50], (k) the endocrine hypothesis [51, 52], (l) the mitochondrial dysfunction [53, 54] and (m) the Golgi

Many of those hypotheses are basely interrelated, such as the amyloid hypothesis and the oxidative stress ones [58, 59], the amyloid and the tau hypothesis [60], the oxidative stress and the mitochondrial dysfunction [61], the mitochondrial dysfunction, energy deficiency and oxidative stress [61, 62], the mitochondria dysfunction and the synaptic pathology [22, 63], the tau pathology and the vascular hypothesis [64], the cholinergic dysfunction and the amyloid hypothesis [65], amyloid, tau and neurodegeneration hypothesis [66], the mitochondria and the dendritic hypothesis [67–69] and the immune reactions, microglia, tau, Aβ peptide, lipid processing and neurodegeneration

Mitochondria hypothesis advocates in favor of the important role that mitochondrial dysfunction may play in the early stages of Alzheimer's disease [21] by inducing energy deficiency and oxidative stress [22], which would be associated with β-amyloid (Aβ) neurotoxicity. It is well known that mitochondria, which has been defined as organelles in tissue culture since 1914 [74] are normally involved in aging

and the synapses of neurons are observed in electron microscopy, even in the initial stage of the disease [19] in areas with minimal typical Alzheimer's pathology, namely aggregations of Aβ peptide and neurofibrillary tangles. The majority of the alterations of the organelles in Alzheimer's disease particularly concern the Golgi complex [19], the microtubules, the synaptic vesicles and mostly the

**36**

This electron microscope study is based on examination of 25 brains obtained at autopsy 2–7 hours after death at a room temperature of 40°C. All of the brains were derived from patients aged 55–80 years, who have had a history of dementia, which was definitely diagnosed 1 or 3 years prior to the end of their life.

The patients fulfilled on repeated clinical examinations and assessments all the psychological, psychiatric and neurological criteria of AD [84–86]. The patients have had 18 years of education, and had a fluency in their native language, two of them being also bilingual with equal fluency in both of the languages. The usual diagnostic assessment was based on the medical history, the physical examination, including cardiological investigation, neurological examination, psychiatric evaluation and detailed neuropsychological testing.

The cognition of the patients was evaluated by battery of neuropsychological testing [87], including mini mental state examination (MMSE) [88, 89], dementia rating scale (DRS) [90, 91], ADAS-COX test [92, 93] and the brief memory executive test (BMET) [94].

All the patients underwent an EEG examination and a carotid examination by duplex Doppler. Neuroimaging was performed including computerized tomography (CT), magnetic resonance imaging (MRI) of the brain and a single-photon emission computed tomography (SPECT) [95]. All the methods of clinical and laboratory investigations were evocative for Alzheimer's disease. The patients passed away due to heart arrest.

In addition, we dissected and examined in electron microscopy 25 brains, which were unremarkable from the neuropathological point of view, derived from apparently healthy individuals of the same age range with the AD patients, using them as normal controls.
