*3.2.1. TLRs and Aβ peptide in AD*

need to express several types of receptors. Moreover, considering that harm/damage signals can be both exogenous, such as those from bacteria and viruses, and endogenous, such as those from DNA or ATP, these receptors should be able to interact with a wide range of these elements. Among the latter, TLRs constitute a key element of the innate immune response related to sterile inflammatory pathological processes, such as AD and PD. It is important to highlight that even when it was initially considered an immune-privileged system, because of its high specialisation and partial isolation from the rest of the organism, the central nervous system (CNS) is able to generate full-range immune responses. In this context, microglia and astrocytes are responsible for immune surveillance in the CNS, with microglia being the only immune-derived cells within the brain. Due to the critical role of the brain microenvironment, evidence suggests that the inflammatory response is tightly controlled to prevent the detrimental effects of an exacerbated process. Indeed, it has been determined that the brain parenchyma constitutes an anti-inflammatory environment with relevant levels of TGF and

TLRs are able to detect DAMPs, which are subcellular components, such as ATP, released into the extracellular media reflecting cell damage. Several members of the TLR family have been described and can be expressed at the plasma membrane, such as TLRs 1, 2, 4, 5, and 6, or in association with endosomes, such as TLRs 3, 7, 8, and 9. Importantly, TLRs are expressed by brain cells, including astrocytes, microglia, neurons and oligodendrocytes, with microglia and neurons expressing all TLR subtypes and astrocytes expressing a more limited repertoire, including TLR2, TLR3, TLR4, TLR9 and TLR11 [59, 60]. Briefly, the TLR-mediated modulation of the inflammatory response begins with the recruitment of myeloid differentiation factor 88 (MyD88), causing activation of the IL-1 receptor-associated kinase (IRAK) family of proteins. IRAK activates TNF receptor-associated factor 6 (TRAF6), causing the recruitment of TGFβ-activated kinase 1 (TAK1). TAK1, along with TAK1-binding proteins (TABs), will activate the IKK complex, causing phosphorylation of the IkB factor and the subsequent release of NF-kB to translocate into the nucleus, leading to the expression of NF-kB-related inflammatory genes. Importantly, TLRs 3 and 4 can also signal via a secondary TIR-containing adaptor inducing an IFN-β (TRIF)-mediated pathway. Additionally, in the latter case, NF-kB will be released, but IFN-β will be produced because of the phosphorylation of IFN regulatory factors 3 and 7 (IRF3–7) via IKKe/TANK-binding kinase 1 (TBK1). Independent of the cascade triggered through TLRs, the final outcome will be the production and release of cytokines, chemokines, complement proteins and enzymes, including several members of the IL family, such as IL-1, IL-6, IL-10, IL-11, and IL-12, as well as TNF, TGF, IFN, CCL2, CCL5, CXCL8 and CXCL10 [59–62]. An additional clue about the necessity of tightly controlling this process within a highly specialised organ, such as the brain, emerges from the property of these molecules to further activate TLRs, a situation that can lead to re-activation of the inflammatory

In this regard, the inflammatory component of AD and PD has been demonstrated to be fundamental for both pathological processes. Moreover, it has been shown that both Aβ and SNCA can induce direct activation of the inflammatory response and that their sustained accumulation and aggregation lead to the genesis of a pro-inflammatory environment [21, 63,

IL-10 [57, 58].

52 Recent Advances in Neurodegeneration

**3.2. TLR-mediated neuroinflammatory response**

cascade and a state of chronic inflammation.

Evidence indicates that TLR2 and TLR4 are able to react with Aβ, leading to the release of several pro-inflammatory mediators, such as IL-1β, IL-6, IL-12, TNF-α, cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS) [66]. As noted previously, such receptors are expressed by different cell types present in the brain, suggesting both the whole-brain commitment to the inflammatory response and the potential contribution of all these cells to the further release of pro-inflammatory mediators. In this regard, of the most relevance is the self-perpetuation of the inflammatory cycle induced by the continuous release of these molecules. Some of the pro-inflammatory cytokines, such as IL-6, which can be produced as part of the response to the initial insult (Aβ), can also be a consequence of the secondary effect induced by other cytokines, such as IL-1β [67]. Thus, if this response is not controlled, the environment can be perfectly suited to a sustained pro-inflammatory status that will overwhelm homeostatic mechanisms and damage the surrounding tissue.

Furthermore, Aβ can trigger additional molecular events within neurons. Beyond its proinflammatory effects, it has been demonstrated that Aβ can induce the hyperphosphorylation of tau protein, which will alter the neuronal cytoskeleton, ultimately leading to neuronal apoptosis with the release of further DAMPs [26, 27, 29, 35]. Evidently, this situation can also promote TLR activation, contributing to perpetuation of the inflammatory cycle. Similarly, astrocytes, which express a more limited repertoire of TLRs, are also fundamental for adequate Aβ metabolism. In the case of AD, astrocytes are responsible for the release of ApoE, the Aβ chaperone protein necessary for its removal from the brain. In this context, defective astrocytes, such as inflammatory-challenged astrocytes, or ApoE-related genetic conditions, such as the ApoEε4 allele, can lead to impaired ApoE activity, causing an increase in the Aβ level [31]. Again, these astrocyte-related conditions can compromise the brain's ability to resolve the inflammatory process and further contribute to enhancing a detrimental inflammatory response. In contrast, microglia, as the only representative of the immune system within the brain parenchyma, are the main cells responsible for surveying and initiating the immune response against exogenous and endogenous insults, acting as the macrophages of the brain. Microglia develop a close interaction with neurons through microglial chemokine (C-X-C motif) receptor 1 (CXCR1) and CD200L, with neuronal CX3CL1 and CD200, respectively [68, 69]. In the absence of a challenging stimulus, microglia remain in a non-inflammatory or "resting" state. However, when inflammatory signals, such as the loss of neuronal contact or DAMPs, are detected, microglia undergo morphological and physiological changes leading to an inflammatory or "activated" state. Among the several receptors expressed by microglia, TLRs 1–9 and the co-receptor CD14 are the most important for its activation [21]. Although it has been demonstrated that Aβ directly activates TLR2 and TLR4, it has recently been shown that additional elements are involved in the activity of microglia in response to aggregated forms of Aβ. Complement receptor 1 (CR1), cluster of differentiation 33 (CD33) and triggering receptor expressed on myeloid cells 2 (TREM2) have proven to be necessary for the successful phagocytosis of Aβ [70–72]. Moreover, it has been suggested that TREM2 acts as a receptor for Aβ, thereby modulating the microglial inflammatory response [73]. The relevance of the functions related to TREM2 activity has led us to consider its proteolytic products (soluble TREM2) as potential biomarkers for AD, mainly because sTREM2 levels have been reported to be elevated in the plasma and CSF of AD patients [73–75]. The precise impact of such findings is just emerging, and some discrepancies have already been identified regarding which should be the appropriate approach to a TREM2-related intervention [76, 77].

as synapses, axons and whole cell structures [88–90]. In this context, mitochondrial activity, which is fundamental to sustaining neuronal activity, is one of the major sources of the continuous production of superoxide anions. This highly reactive species, if not neutralised, will severely damage subcellular structures. Under regular conditions, superoxide anions are scavenged as soon as they are produced through hydrogen peroxide formation. However, under altered redox conditions, such as those during ageing, cellular mechanisms to manage both physiological and pathological ROS/RNS production are overwhelmed [12–15]. Thus, AD and PD cause additional pressure on the mitochondria in an already poorly balanced system.

Molecular Basis of Neurodegeneration: Lessons from Alzheimer's and Parkinson's Diseases

http://dx.doi.org/10.5772/intechopen.81270

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In this regard, both Aβ and SNCA have been demonstrated to be able to alter mitochondria. While Aβ has been found within mitochondria, indicating a direct effect on mitochondrial functionality [91, 92], SNCA can impair mitochondrial function mainly via altered cell trafficking. Indeed, it has recently been suggested that the cytoskeletal alterations induced by SNCA will modulate the localization of dynamin-related protein 1 (Drp1), a key protein related to mitochondrial dynamics and whose malfunction will lead to mitochondrial dysfunction [93, 94]. Complimentarily, Aβ, and probably SNCA, can induce ER stress, leading to the intracellular release of Ca2+, which can increase the mitochondrial challenge, leading to further ROS/RNS production and causing the subsequent activation of classical pro-apoptotic pathways, such as ROS-mediated apoptosis through apoptosis signal-regulated kinase (ASK1) and activation of the B cell lymphoma 2 (BCL2)-beclin 1 (BECN1) complex [91, 92]. It should not be forgotten that ROS/RNS can trigger the inflammatory response in surrounding cells, such as glial cells and neighbouring neurons, in a TLR- and DAMP-mediated manner. Moreover, it is possible that prior to the pathological process, these aged individuals have some degree of inflammation, oxidative stress and mitochondrial impairment, which might facilitate the establishment and/

**4. Wnt signalling in the context of AD and PD anti-inflammatory** 

Currently, neurodegenerative disorders, especially AD and PD, are considered a major concern in public health because of the ageing of the global population. Although some progress has been made regarding pharmacological strategies, regrettably, no effective therapies are currently available to stop or reverse these pathologies. Among the alternative approaches to overcome such situations, the identification and further modulation of key cellular pathways involved in the pathophysiology of neurodegenerative disorders should not be underestimated. In this regard, even when it is well recognised that inflammation is one of the most relevant features of AD and PD, anti-inflammatory therapies have remained overlooked, although some epidemiological data have suggested a significant effect in terms of risk reduction with the use of some nonsteroidal anti-inflammatory drugs (NSAIDs) [95, 96]. Interestingly, the main effects related to the use of such a family of drugs have been observed prior to the onset of pathology; however, the efficacy of an anti-inflammatory therapy cannot be fully discarded. Indeed, the reasons behind the failure of some clinical trials exploring the beneficial effects of NSAIDs in AD and PD have not been properly addressed [97]. Moreover,

or progression of both diseases.

**therapeutics**
