**2.1. Alzheimer's disease**

In general terms, AD compromises patient memory and cognitive performance. Initially manifesting as mood instability, the clinical scenario progresses from the compromise of short-term memory to the loss of long-term memory. As superior functions are lost, patients become absolutely dependent on a caregiver to complete even the most elementary tasks. Atrophy of the frontal cortex, limbic area and hippocampus due to neuronal death are the basis of these clinical alterations. Histopathologically, AD shows the extracellular accumulation of amyloid β (Aβ) plaques and the intraneuronal formation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein [26]. However, even when these molecular events are considered the hallmarks of AD, these alterations are accompanied by an increased oxidative stress status, mitochondrial dysfunction and a chronic inflammatory response, among others, which ultimately serve to explain the synaptic damage, neuronal loss and neuronal circuitry breakdown [26, 27].

Relevantly, although AD constitutes an age-related disorder, an early onset presentation linked to the genetic background should not be omitted. In this regard, while late-onset AD (LOAD) is associated with patients over 65 years old, familial or early-onset AD (EOAD) appears before this threshold, with cases reported as soon as 30 years old. Of course, in EOAD, there is a relevant genetic background in at least three genes (amyloid precursor protein, *APP*; presenilin 1, *PSEN1*; and presenilin 2, *PSEN2*). On the other hand, in the case of LOAD, age and lifestyle are considered to be the main causative factors. Importantly, the apolipoprotein E epsilon 4 (ApoEε4) allele has been identified as a relevant risk factor for both presentation forms [28].

Independent of the presentation form, and as noted previously, Aβ deposition and NFT formation constitute the key molecular features of AD. Moreover, considering that each of the additional pathological alterations often observed during progression of the pathological process can be derived from each of these two hallmarks, each of them has led to the development of individual hypotheses. Although the crosstalk between the amyloid and tau hypotheses is evident, it must be noted that the scientific community has not yet agreed on which one encompasses the whole spectrum of the disease, and the aetiological trigger of the pathological molecular cascade remains unknown.

Even with several additional hypotheses having been developed since the first description of AD by Dr. Alois Alzheimer, including the "cholinergic hypothesis" [29], from our limited expertise in the field, we approach AD considering the increased production and subsequent accumulation of Aβ within the brain as the starting point. Indeed, synaptic failure, mitochondrial dysfunction, tau hyperphosphorylation, glial activation and neuronal death, among

homeostatic imbalance verified during abnormal ageing.

**Figure 2.** Alzheimer's disease (AD) and Parkinson's disease (PD). Pathological milieu overview. AD and PD are highly complex disorders. In both cases, in addition to the molecular hallmarks, cellular alterations are verified. Although several risk factors have been identified, the aetiology of both disorders is still unknown. AD is characterised by neuronal loss, mainly in the hippocampus. The pathognomonic feature of AD is the deposition of amyloid-β aggregates (senile plaques) and the formation of neurofibrillary tangles composed of hyperphosphorylated tau protein. These molecular alterations not only affect neurons but also induce microglial and astrocytic activation, leading to the release of several pro-inflammatory mediators. Additionally, cellular and molecular events will cause an increased production of reactive oxygen/nitrogen species, which will further damage the surrounding neurons and activate the surrounding glial cells, perpetuating the inflammatory response. In contrast, PD is characterised by the loss of dopaminergic circuitry beginning at the basal forebrain (substantia nigra pars compacta (SNpc), nucleus accumbens and ventral tegmental area (VTA)) and spreading to the striatum. The molecular hallmark of PD is the formation of Lewy bodies and neurites, which are composed of aggregated α-synuclein (SNCA), causing severe cellular stress affecting the cytoskeleton, neuronal trafficking and the synthesis of dopamine because of the direct inhibition of tyrosine hydroxylase (TH). SCNA can be exocytosed, causing it to be internalised by astrocytes, where it can further aggregate. Similarly, it will cause microglial activation. Neurons, astrocytes and microglia release pro-inflammatory mediators as well as ROS/RNS. A common feature of both disorders is mitochondrial dysfunction, which can be due to the pathological process or the result of the

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Molecular Basis of Neurodegeneration: Lessons from Alzheimer's and Parkinson's Diseases http://dx.doi.org/10.5772/intechopen.81270 49

systems that can become imbalanced with any additional external/internal stimulus, leading to

In the following sections, we will summarise the most relevant aspects of AD and PD and the key elements of each pathophysiological process in the context of the delicate balance of an

AD and PD constitute the two most common age-related neurodegenerative disorders [1, 25], and their prevalence is expected to increase together with the ageing of the human population [1]. Although they are different entities, both disorders share some similarities regarding

In general terms, AD compromises patient memory and cognitive performance. Initially manifesting as mood instability, the clinical scenario progresses from the compromise of short-term memory to the loss of long-term memory. As superior functions are lost, patients become absolutely dependent on a caregiver to complete even the most elementary tasks. Atrophy of the frontal cortex, limbic area and hippocampus due to neuronal death are the basis of these clinical alterations. Histopathologically, AD shows the extracellular accumulation of amyloid β (Aβ) plaques and the intraneuronal formation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein [26]. However, even when these molecular events are considered the hallmarks of AD, these alterations are accompanied by an increased oxidative stress status, mitochondrial dysfunction and a chronic inflammatory response, among others, which ultimately serve to explain the synaptic damage, neuronal loss and neuronal circuitry breakdown [26, 27]. Relevantly, although AD constitutes an age-related disorder, an early onset presentation linked to the genetic background should not be omitted. In this regard, while late-onset AD (LOAD) is associated with patients over 65 years old, familial or early-onset AD (EOAD) appears before this threshold, with cases reported as soon as 30 years old. Of course, in EOAD, there is a relevant genetic background in at least three genes (amyloid precursor protein, *APP*; presenilin 1, *PSEN1*; and presenilin 2, *PSEN2*). On the other hand, in the case of LOAD, age and lifestyle are considered to be the main causative factors. Importantly, the apolipoprotein E epsilon 4 (ApoEε4) allele has been identified as a relevant risk factor for both presentation forms [28].

Independent of the presentation form, and as noted previously, Aβ deposition and NFT formation constitute the key molecular features of AD. Moreover, considering that each of the additional pathological alterations often observed during progression of the pathological process can be derived from each of these two hallmarks, each of them has led to the development of individual hypotheses. Although the crosstalk between the amyloid and tau hypotheses is evident, it must be noted that the scientific community has not yet agreed on which one encompasses the whole spectrum of the disease, and the aetiological trigger of the

failure of biological systems and the development of diverse pathological hallmarks.

**2. Molecular event-driven neurodegeneration: lessons from** 

aged system.

48 Recent Advances in Neurodegeneration

**AD and PD**

pathophysiological processes (**Figure 2**).

pathological molecular cascade remains unknown.

**2.1. Alzheimer's disease**

**Figure 2.** Alzheimer's disease (AD) and Parkinson's disease (PD). Pathological milieu overview. AD and PD are highly complex disorders. In both cases, in addition to the molecular hallmarks, cellular alterations are verified. Although several risk factors have been identified, the aetiology of both disorders is still unknown. AD is characterised by neuronal loss, mainly in the hippocampus. The pathognomonic feature of AD is the deposition of amyloid-β aggregates (senile plaques) and the formation of neurofibrillary tangles composed of hyperphosphorylated tau protein. These molecular alterations not only affect neurons but also induce microglial and astrocytic activation, leading to the release of several pro-inflammatory mediators. Additionally, cellular and molecular events will cause an increased production of reactive oxygen/nitrogen species, which will further damage the surrounding neurons and activate the surrounding glial cells, perpetuating the inflammatory response. In contrast, PD is characterised by the loss of dopaminergic circuitry beginning at the basal forebrain (substantia nigra pars compacta (SNpc), nucleus accumbens and ventral tegmental area (VTA)) and spreading to the striatum. The molecular hallmark of PD is the formation of Lewy bodies and neurites, which are composed of aggregated α-synuclein (SNCA), causing severe cellular stress affecting the cytoskeleton, neuronal trafficking and the synthesis of dopamine because of the direct inhibition of tyrosine hydroxylase (TH). SCNA can be exocytosed, causing it to be internalised by astrocytes, where it can further aggregate. Similarly, it will cause microglial activation. Neurons, astrocytes and microglia release pro-inflammatory mediators as well as ROS/RNS. A common feature of both disorders is mitochondrial dysfunction, which can be due to the pathological process or the result of the homeostatic imbalance verified during abnormal ageing.

Even with several additional hypotheses having been developed since the first description of AD by Dr. Alois Alzheimer, including the "cholinergic hypothesis" [29], from our limited expertise in the field, we approach AD considering the increased production and subsequent accumulation of Aβ within the brain as the starting point. Indeed, synaptic failure, mitochondrial dysfunction, tau hyperphosphorylation, glial activation and neuronal death, among others, can be explained by the Aβ dynamics [27, 30]. According to this theory, AD results from the increased levels of Aβ, a 37- to 49-amino acid peptide derived from the proteolytic processing of APP, because of an unbalanced production/clearance rate [31–33]. In this regard, under the AD scenario, the non-amyloidogenic processing of APP, carried out by the alpha (α) and gamma (γ) secretases, which leads to the release of soluble APPα (sAPPα) and the p3 fragment, is overwhelmed by amyloidogenic processing, with beta (β) secretase (BACE1) as the main player, leading to an increased release of the neurotoxic Aβ peptide [30, 33]. On the other hand, under balanced physiological conditions, Aβ is cleared to the blood stream and cerebrospinal fluid (CSF), with the involvement of ApoE, the Aβ chaperone [30, 31], through several transporter proteins, including members of the ATP-binding cassette family of transporters, such as ABCB1, ABCC2 and ABCG4, and the low-density lipoprotein receptor-related protein/ApoE receptor (LRP/APOER), the main receptor responsible for Aβ clearance through the blood-brain barrier (BBB) [30, 34–36]. ApoE deficiency/incompetence (ApoEε4), altered Aβ-related transporter expression, choroid plexus and BBB damage will impair Aβ clearance, increasing brain Aβ levels. Additionally, the reduced activity of Aβ-degrading enzymes, such as disintegrin and metalloproteases (ADAM 9, 10 and 17A) and neprilysin, will further contribute to its accumulation within the brain [32, 33, 37–40]. At this point, the increased levels of Aβ will favour its self-aggregation, leading to the formation of different Aβ species, such as oligomers, fibrils and/or even larger aggregates, such as plaques [26, 29]. Moreover, the presence of APP together with its proteolytic machinery within the subcellular compartments, such as the Golgi and endoplasmic reticulum (ER), as well as the presence of Aβ peptide in the mitochondria, suggests that the intracellular APP dynamics can also be part of the pathological scenario along with the extracellular accumulation of Aβ peptide. Indeed, it has been demonstrated that in the presence of high levels of Aβ, the peptide can enter the cell through the presynapticα 7 nicotinic acetylcholine receptor and that this influx could be the basis for tau hyperphosphorylation, thereby causing neurite atrophy and synapse failure [30].

mainly regarding exposure to different types of chemicals, including agrochemicals and drugs [25, 44]. With the increase in life expectancy, the global PD prevalence is expected to

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As noted previously, independent of the presentation form, SNCA aggregates constitute the pathological hallmark of PD. In this regard, SNCA corresponds to a monomeric 140-amino acid protein localised at the presynaptic terminal, which is thought to be involved in the recycling of synaptic vesicle pools [45–47]. Although 50% of the protein can be found at the cytosolic level within the terminals, the remaining SNCA is associated with the membrane of both vesicles and early endosomes. Indeed, SNCA has been described as a chaperone protein of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins [48]. However, the mechanisms related to the interaction of SNCA with SNARE or additional presynaptic proteins, such as Piccolo/Bassoon or Rab, and its function in regulating the dynamics of the synaptic terminal are still unknown [43, 49, 50]. Under pathological conditions, SNCA changes from a monomeric membrane-associated protein to an unbound monomer capable of forming β-sheet aggregates, which ultimately will form SNCA amyloid fibrils [50–52]. Moreover, SNCA can not only interfere with tyrosine hydroxylase, the dopamine synthesis enzyme, affecting both its expression and activity [53], but also interact with the dopamine transporter (DAT) [54]. At this point, and considering the altered synaptic vesicle dynamics, the dopaminergic synapse is severely compromised, constituting the basis of the PD synaptopathy. Additionally, similar to AD, this initial molecular event can be related to the additional features observed during the pathological process, including mitochondrial

Immunocompetence constitutes a fundamental feature for ensuring the preservation of any living organism. The rapid and coordinated elimination of potentially harmful elements is critical to maintain organism homeostasis and prevent irreversible damage to biological systems. In this regard, the innate and adaptive immune systems constitute the two subsystems that able to detect and induce a primary unspecific response to pathogens, coordinate a secondary response and develop an immune memory, the hallmark of adaptive immunity. As the first response element, the innate immune system depends on the effectiveness of several unspecific elements, including physical and chemical barriers, the complement system, the activity of surveillance cells, and inflammation. Through these complementary elements, a fundamental physiological process is triggered to constrain the insult and repair the damage. In general, whether because of a pathogen, toxic and/or damaged-cell end-products, the cellular microenvironment will change, leading to the activation of immunocompetent cells and causing the release of pro- and anti-inflammatory cytokines, such as tumour necrosis factor 1α (TNF-1α), interleukins (IL-1, IL-8, IL-10), interferon γ (INF-γ) and transforming growth factor 1 (TGF-1), to orchestrate a coordinated response against the primary insult, limiting its damage [55, 56]. Importantly, to appropriately answer signals of harm/damage, surveillance cells

dysfunction, increased oxidative stress, and neuroinflammation.

**3. Pathophysiological cascade in AD and PD**

**3.1. Inflammation and the CNS**

double over the next decade.

#### **2.2. Parkinson's disease**

PD is the second most common neurodegenerative disorder and can be classified as a synucleinopathy. It is characterised by failure of the dopaminergic circuitry because of the loss of dopaminergic neurons of the substantia nigra pars compacta (SNpc). Histopathologically, PD shows neuronal inclusions of aggregated α-synuclein (SNCA) protein in both the cell soma and neurites, forming Lewy bodies and neurites [25]. Although the effects of the loss of dopaminergic neurons help to explain the symptomatology, mainly associated with motor compromise, the mechanisms by which SNCA aggregates in relation to the whole molecular and clinical picture have remained elusive. Ranging from non-motor symptoms, including hyposmia and sleep disturbances, PD progresses to bradykinesia and rigidity and can be accompanied by impairments in memory, mainly prospective memory [25, 41, 42].

Similar to AD, genetic background also accounts for a small proportion of PD cases worldwide. β-Glucocerebrosidase (GBA), leucine-rich repeat kinase 2 (LRRK2), SNCA, parkin (PRKN), protein/nucleic acid deglycase (DJ1) and phosphatase and tensin homologue (PTEN)-induced putative kinase 1 (PINK1) have been recognised as the most relevant genes associated with PD presentation [25, 43]. On the other hand, sporadic PD has been related to age and lifestyle, mainly regarding exposure to different types of chemicals, including agrochemicals and drugs [25, 44]. With the increase in life expectancy, the global PD prevalence is expected to double over the next decade.

As noted previously, independent of the presentation form, SNCA aggregates constitute the pathological hallmark of PD. In this regard, SNCA corresponds to a monomeric 140-amino acid protein localised at the presynaptic terminal, which is thought to be involved in the recycling of synaptic vesicle pools [45–47]. Although 50% of the protein can be found at the cytosolic level within the terminals, the remaining SNCA is associated with the membrane of both vesicles and early endosomes. Indeed, SNCA has been described as a chaperone protein of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins [48]. However, the mechanisms related to the interaction of SNCA with SNARE or additional presynaptic proteins, such as Piccolo/Bassoon or Rab, and its function in regulating the dynamics of the synaptic terminal are still unknown [43, 49, 50]. Under pathological conditions, SNCA changes from a monomeric membrane-associated protein to an unbound monomer capable of forming β-sheet aggregates, which ultimately will form SNCA amyloid fibrils [50–52]. Moreover, SNCA can not only interfere with tyrosine hydroxylase, the dopamine synthesis enzyme, affecting both its expression and activity [53], but also interact with the dopamine transporter (DAT) [54]. At this point, and considering the altered synaptic vesicle dynamics, the dopaminergic synapse is severely compromised, constituting the basis of the PD synaptopathy. Additionally, similar to AD, this initial molecular event can be related to the additional features observed during the pathological process, including mitochondrial dysfunction, increased oxidative stress, and neuroinflammation.
