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

DOI: 10.5772/intechopen.72612

A. Raquel Esteves, Diana F. Silva, Daniel Santos, Emanuel Candeias, Filipa Filipe and Sandra M. Cardoso A. Raquel Esteves, Diana F. Silva, Daniel Santos, Emanuel Candeias, Filipa Filipe and Sandra M. Cardoso Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

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

#### **Abstract**

Mitochondria are exceptionally primed to play a key role in neuronal cell survival since they are involved in energy production and function as the metabolic center of cells. Several findings provide evidence for the role of mitochondria in neurodegeneration associated with Alzheimer's and Parkinson's diseases (AD and PD). Recent data highlight the role of mitochondrial proteins and mitochondrial reactive oxygen species in the intracellular signaling that regulates innate immunity and inflammation. In this chapter, we will discuss the relevance of the interplay between mitochondria and innate immunity, focusing on mitochondrial damage-associated molecular patterns (DAMPs) and how they can activate innate immunity and elicit AD and PD neurodegenerative process.

**Keywords:** mitochondria, neuronal innate immunity, Alzheimer's disease, Parkinson's disease, damage-associated molecular patterns

#### **1. Introductory remarks**

Mitochondria, derived from an ancestral bacterial endosymbiosis, are important cellular organelles in all cell types, but particularly important in the nervous system, since they are the major source of energy for the brain. Mitochondria are essential for neuronal function and neuronal processes, such as calcium (Ca2+) homeostasis, maintenance of plasma membrane potential, apoptosis, axonal and dendritic transport, release and re-uptake of neurotransmitters at synapses, among others [1, 2]. The brain is particularly vulnerable to oxidative stress due to its high lipid content, its high oxygen demand and its low levels of antioxidant defenses. Therefore, any abnormalities in mitochondria function may impact the aging process and also potentiate the onset of age-dependent neurodegenerative disorders [3, 4].

© 2016 The Author(s). Licensee InTech. 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. © 2018 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.

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].

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]. 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

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

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

139

correlated somehow with the severity of cognitive impairment in AD patients [24].

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

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

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.
