**2. Alzheimer's disease hallmarks**

AD is one of the most frequent age-related neurodegenerative disorder, characterized by neuronal loss and gradual cognitive demise. It is the major cause of dementia in the elderly [11], predominantly affects more women than men [12], and is expected that the number of people with AD will triple by the year 2050 [13]. Patients with AD show an impaired ability to perform everyday tasks and often experience psychiatric, emotional and personality disturbances [14]. Two well-known abnormal protein aggregates in the brain of the patients, cerebral cortex and hippocampus, characterize AD pathologically: the neuritic plaques that are extracellular and composed of insoluble amyloid β peptides (Aβ) and neurofibrillary tangles that are intracellular aggregates, mostly consisted of phosphorylated tau, a microtubuleassociated protein [15]. It is assumed that oligomers can induce toxicity for neurons causing synaptic dysfunction, neuroinflammation and oxidative stress [16, 17].

Several authors have mentioned that mitochondrial dysfunction and oxidative damage occur in the AD brain before the onset of Aβ pathology. Mitochondrial dysfunction was reported in brain neurons, platelets and fibroblasts from AD patients and in transgenic AD mice models. These mitochondrial abnormalities have been reported in neurons and astrocytes, suggesting that both types of cell might be affected in brains of AD patients [18]. For example, it has been described in post-mortem AD brains, a deficit of cytochrome c oxidase (COX) in hippocampus, frontal, temporal, occipital and parietal lobes [3]. Additionally, it is recognized that mitochondrial DNA (mtDNA) is also involved in the mitochondrial dysfunction having a determinant role in AD pathogenesis. When patient's mtDNA is transferred into mtDNA-deficient cell lines, the originated 'cybrids' reproduce the respiratory enzyme deficiency that occurs in the brain and other tissues in AD, suggesting this defect is carried in part by mtDNA abnormalities [19].

In Alzheimer's disease (AD) and Parkinson's disease (PD), it has been described that mitochondrial metabolism and dynamics are affected not only in susceptible brain areas but also in peripheral cell models, namely platelets, fibroblasts and lymphocytes. Additionally, it was shown in AD and PD cellular and animal models that mitochondrial network is highly fragmented. Mitochondrial fission is required to selectively target dysfunctional mitochondria for degradation by the lysosome in a process called mitophagy [5, 6]. Nevertheless, it was recently proven that mitochondrial fission leads to the exposure of the inner membrane phospholipid, cardiolipin, which serves an important defensive function for the elimination of damaged mitochondria [7]. Since cardiolipin is found only in mitochondrial and bacterial membranes, it is considered a mitochondrial-derived damage-associated molecular pattern (DAMP) that is detected by a Nod-like receptor (NLR), the nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3 (NLRP3) inflammasome Nlrp3 [8]. NLR and toll-like receptors (TLR) are patternrecognition receptors that recognize pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide and short-chain fatty acids, and DAMPs that are responsible for the initiation of innate immune responses. NLR and TLR activation trigger the production of proinflammatory cytokines and antimicrobial peptides (AMPs) [9]. So, it is perceived that also neuronal cells are able to mount an innate immune response. Neurons express critical Toll/interleukin-1 receptor (TIR) domain-containing adaptors that transduce signals of TLR, regulating the expression of various cytokines. Indeed, TLR 3 and 7, localized in the neuronal endosomal compartment, play a role in neurite outgrowth. It is assumed that the cytokines produced by neurons may be just enough to recruit and activate local microglia and may not cause global brain inflammation [10]. Overall, mitochondria play a central role in metabolism, thus allowing the maintenance of cellular homeostasis. In this chapter, we will discuss how mitochondria can regulate neuronal innate immunity and how this impact age-related neurodegenerative disorders, such as AD and PD.

AD is one of the most frequent age-related neurodegenerative disorder, characterized by neuronal loss and gradual cognitive demise. It is the major cause of dementia in the elderly [11], predominantly affects more women than men [12], and is expected that the number of people with AD will triple by the year 2050 [13]. Patients with AD show an impaired ability to perform everyday tasks and often experience psychiatric, emotional and personality disturbances [14]. Two well-known abnormal protein aggregates in the brain of the patients, cerebral cortex and hippocampus, characterize AD pathologically: the neuritic plaques that are extracellular and composed of insoluble amyloid β peptides (Aβ) and neurofibrillary tangles that are intracellular aggregates, mostly consisted of phosphorylated tau, a microtubuleassociated protein [15]. It is assumed that oligomers can induce toxicity for neurons causing

Several authors have mentioned that mitochondrial dysfunction and oxidative damage occur in the AD brain before the onset of Aβ pathology. Mitochondrial dysfunction was reported in brain neurons, platelets and fibroblasts from AD patients and in transgenic AD mice models. These mitochondrial abnormalities have been reported in neurons and astrocytes, suggesting that both types of cell might be affected in brains of AD patients [18]. For example, it has been

synaptic dysfunction, neuroinflammation and oxidative stress [16, 17].

**2. Alzheimer's disease hallmarks**

138 Mitochondrial Diseases

Neuroinflammation has been implicated in AD etiology, but its contribution to disease progression is still not yet understood [20]. Astrocytes and microglial cells are the main type of cells involved in inflammatory responses in the central nervous system (CNS) after infection or injury occurs. Indeed, in this process, cellular and molecular immune components, such as cytokines, are important players, which may lead to the activation of glial cells (microglia and astrocytes) [21]. Several studies have described that Aβ, pathogenic infection or cellular debris triggers an initial inflammatory stimulus, which activates the microglia, allowing the maintenance of neuronal plasticity and synaptic connectivity [22]. Data suggest that microglia internalize and degrade Aβ deposits, helping its clearance from the brain. However, during disease process, microglia acquire a 'toxic' phenotype due to chronic activation and continue the production of proinflammatory mediators [23]. In animal models and human brain tissue, both neuritic plaques and neurofibrillary tangles colocalize with activated glial cells. Different studies have reported pathological astrogliosis, in both AD patients and transgenic animal models brains, characterized by an increased glial fibrillary acidic protein (GFAP) and distinct cellular hypertrophy, which is correlated somehow with the severity of cognitive impairment in AD patients [24].
