**3.1. Inflammation and the CNS**

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].

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,

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

**2.2. Parkinson's disease**

50 Recent Advances in Neurodegeneration

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 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 IL-10 [57, 58].

64]. Indeed, during the recent year, the modulation and control of the inflammatory cascade have emerged as target elements of future therapeutic interventions aimed at improving AD

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

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

53

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 over-

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

whelm homeostatic mechanisms and damage the surrounding tissue.

and PD outcomes [34, 64, 65].

*3.2.1. TLRs and Aβ peptide in AD*

#### **3.2. TLR-mediated neuroinflammatory response**

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 cascade and a state of chronic inflammation.

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, 64]. Indeed, during the recent year, the modulation and control of the inflammatory cascade have emerged as target elements of future therapeutic interventions aimed at improving AD and PD outcomes [34, 64, 65].
