**2.1. The role of mitochondrial dysfunction in Alzheimer's disease etiology**

Despite its elusive origin, mitochondrial dysfunction is long recognized as a striking feature of sporadic AD, mediating cell pathways that sustain the disorder progression. Brain bioenergetic function is compromised in AD. Images from fluorodeoxyglucose positron emission tomography (FDG-PET) scan show that glucose utilization is significantly lower in AD subjects as compared to age-matched controls in the cortex and the posterior cingulate brain regions [25]. This bioenergetic compromise correlates with decreased COX activities measured in post-mortem brain tissue from AD patients [26]. Mitochondrial deficits in AD have been described not only in the brain but also in peripheral tissues. COX activity was found decreased in platelets and lymphocytes from AD subjects [27–30]. This COX deficiency correlates with decreased oxygen consumption first described in AD subject's brain, where PET scans showed decreased cerebral metabolic rate of oxygen (CMRO2) [31]. Mitochondrial respiration is also compromised in peripheral blood mononuclear cells [32], and in cytoplasmic hybrid (cybrid) cell lines [33], generated by the fusion of mitochondrial DNA (mtDNA) depleted cells with platelets from AD subjects [34]. These cell lines elucidated on the relevance of mtDNA in AD pathology, since the main features of the disease are recapitulated [33, 35, 36]. The same observation was made in a number of transgenic mice models that carry mutations linked to AD familial forms [37–39].

Along with impaired mitochondrial function, it has been widely demonstrated that mitochondria from AD tissues and models have decreased mitochondrial membrane potential (∆Ψmit) [40]. Cumulative evidence consistently showed a positive correlation between ∆Ψmit and reactive oxygen species (ROS) production [41]. In the case of neurodegenerative disorders, such as AD, associated with dysfunctions of the respiratory chain components, lower ∆Ψmit and decreased activity of the respiratory chain are observed with a simultaneous increase in ROS production [42]. The primary ROS in mitochondria is the superoxide radical anion O2 –., mainly produced at complexes I and III [43], which is rapidly converted to H<sup>2</sup> O2 by mitochondrial dismutases, superoxide dismutase (SOD). Regardless the contradictory data on the contribution of COX deficiency to ROS production [44, 45], oxidative damage is an utterly feature of AD, from human samples to cellular and animal models [36, 46–48]. Evidence show that mitochondrial dysfunction and ROS production are accentuated by Aβ, a 4 kDa protein, derived from a larger protein, amyloid β-protein precursor (βAPP), that is overproduced during AD progression. Aβ interacts with mitochondrial proteins, namely ABAD, causing increased ROS production, mitochondrial dysfunction and neuronal death [49, 50]. These changes in mitochondrial metabolism seem to be related with morphological alteration of mitochondria of AD tissues and models. Electron microscopy images from AD brain tissue show mitochondria with reduced dimensions and disrupted *cristae* [51]. Similarly, mitochondria from AD subjects transferred to mtDNA depleted cell into cybrids at an ultrastructural level are small and have a swollen-like structure [52], with a fragmented mitochondrial network that correlates with increased mitochondrial content of dynamin-related protein 1 (DRP1) [53] a key protein for mitochondrial division [54]. Concerning mitochondrial content/mass in AD neurons, the matter is not as straight forward [55]. Vulnerable neurons have a decrease in functional mitochondria, but mtDNA is increased [51]. In accordance it was observed, in AD cybrids, an increase in mtDNA content [33]. This increment was first explained as a compensatory response to counteract the loss of mtDNA transcription efficiency [51], but data gathered on the subject point to decreased mitochondria degradation through autophagy (mitophagy), with imprisoned mitochondria within autophagic vacuoles that are accessible for mtDNA detection [53]. A number of studies have shown autophagy dysfunction as a driving force of AD progression, with important impact on Aβ deposition and plaque formation [56–60]. In human brain samples, it could be observed a massive accumulation of autophagic vacuoles and lysosome-related vesicles, which led to the conclusion of simultaneous induction and impairment of autophagy [56, 61]. Purified autophagic vesicles contain βAPP and the proteases responsible for its cleavage [56]. Aβ peptides are produced by sequential proteolytic processing of βAPP by β-secretase (BACE) and γ-secretase complex (presenilin and nicastrin) [62, 63]. These accumulated vacuoles cause swellings along dystrophic neurites and potentiate Aβ production and aggregation [64], which gradually form the extracellular amyloid plaques, one of the most prominent brain pathological hallmarks of AD. It is reasonable to argue that stimulating autophagy would clear the cell waste materials. Although some contradictory data were published, in opposition of ameliorating Aβ pathology, stimulating autophagy, either chemically or starvation-induced, fails to degrade accumulating Aβ and worsens cell function in *in vivo* models [65]. The driver of such failure is the microtubule network, along which autophagic vesicles are transported towards lysosomes, for degradation of cell waste. Mitochondrial metabolism failure compromises microtubule proper dynamics. Destabilized microtubule cytoskeleton negatively impacts autophagic vesicles retrograde transport towards lysosomes and promotes microtubule-associated protein Tau to detach and undergo phosphorylation [5]. Tau is the main component of paired helical filaments (PHF) that form neurofibrillary tangles found in AD brains [66] and is a microtubule-associated protein (MAP) that promotes microtubule assembly and stabilization [67–69]. Ultrastructural analysis performed in AD neurons found that the number and total length of microtubules are decreased in AD subjects [70]. In AD cybrids, microtubule network is disrupted with increased free tubulin

content, and this correlates with increased Tau phosphorylation, comparing with control cybrids [53]. Targeting microtubule stability is able to protect cells from Tau and Aβ-induced toxicity and

Mitochondria at the Base of Neuronal Innate Immunity in Alzheimer's and Parkinson's Diseases

http://dx.doi.org/10.5772/intechopen.72612

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The role of neuroinflammation in AD dates back to 1907, to the original report of Alois Alzheimer, with microglia surrounding Aβ plaques, thus showing a close relation between the pathway and the disease [73]. Twenty-five years after the postulation of Selkoe and Hardy, the amyloid cascade hypothesis is still the main hypothesis for AD pathogenesis. It is a fact that all AD patients undergo progressive Aβ deposition, and moreover, the sequence of major pathogenic events leading to AD proposed by the amyloid cascade hypothesis is perfectly aligned with the dominantly inherited forms of AD. However, different mechanisms have to be considered to explain the development of AD in sporadic cases, which constitute the vast majority of the cases [74]. Even though Aβ peptide and tau protein oligomers are considered the major contributors to disease progression and the deposition of Aβ occurs decades before any other alterations, there are some missing links between the accumulation and oligomerization of Aβ and tau pathology, synaptic dysfunction and cognitive decline [15, 75]. In this follow-up, neuroinflammation is consistently reported to be deregulated in AD and to facilitate disease progression [76, 77]. Indeed, various forms of Aβ oligomers and aggregates are detected by numerous receptors (TLRs), receptor for advanced glycated end-products (RAGE), CD14, CD36, CD47, α6β1 integrin, class A scavenger receptor and NOD-like receptor family pyrin domains (NLRP) that activate innate immunity response (mainly via MAPK/Erk and NF-κB-mediated signaling) [22, 78–80]. In neurodegenerative diseases, such as AD, the inflammatory response starts by innate immune system activating monocytes (in periphery) and microglial cells, astrocytes and perivascular cells (in the CNS) [81]. Microglia, the resident macrophages of the CNS, play an active role surveying the brain for pathogens and maintaining neuronal plasticity and synaptic connectivity [82]. In AD, stimulation of microglia involves the microglial polarization to a M1 phenotype that triggers the production of proinflammatory cytokines (TNF-α, IL-1, IL-6, IL-12 and IL-18) [83, 84] and chemokines (CCL2, CCR3, CCR5) [85, 86] and is accompanied by impaired phagocytic capacity [87]. Interestingly, deregulation of Aβ clearance from the CNS is a key pathogenic mechanism in pathology progression, whereas microglial phagocytosis activation plays a crucial role (in combination with the endolysosomal pathway, being Aβ enzymatically digested by neprilysin, insulin-degrading enzyme and matrix metalloprotease proteases) and is controlled by two microglial cell surface receptors: TREM2 (positive regulator) and CD33 (negative regulator) [88, 89]. Moreover, caspases are known mediators of apoptosis, but they also regulate inflammation. Upon binding of Aβ to NLRP, there is an inflammasome-dependent activation of caspase-1 that mediates the production of mature IL-1β by cleavage of an inactive pro-IL-1β peptide [90, 91]. Therefore, elevated concentrations of active caspase 1 detected in the brains of patients with AD [92] are in accordance with the increased NLRP3 activation observed in monocytes from AD patients [93]. In addition, mitochondrial DAMPs were shown to increase AD-associated biomarkers, such as App mRNA, APP protein and Aβ1–42 levels, in SH-SY5Y and mice brains [94, 95]. Together, these studies suggest that mitochondria and mitochondrial DAMPs have the potential to promote inflammation in the brain, with important conse-

restores autophagy function in a variety of AD models [71, 72].

quences relevant for neurodegenerative disorders such as AD.

**2.2. Immune response in Alzheimer's disease**

content, and this correlates with increased Tau phosphorylation, comparing with control cybrids [53]. Targeting microtubule stability is able to protect cells from Tau and Aβ-induced toxicity and restores autophagy function in a variety of AD models [71, 72].
