**4.2 Parkinson's disease**

*Toll-like Receptors*

**4.1 Alzheimer's disease**

and CXCL10, among others [4, 11, 18, 19].

The main objective of these TLR-mediated processes is to regulate the expression of several pro-inflammatory and anti-inflammatory mediators including IL-1, IL-6, IL-10, IL-11, IL-12, tumor necrosis factor (TNF), TGF, IFN, CCL2, CCL5, CXCL8,

Additionally, TLR activation can also signal through complementary molecular pathways. Indeed, TAK1 activation also induces nemo-like kinase (NLK) and the c-Jun N-terminal kinases (JNK) pathway [18–21]. Similarly, MyD88 can signal through the phosphatidylinositide-3 kinase (PI3K)/Akt pathway, modulating the activity of the glycogen synthase kinase 3 β (GSK3β) [22, 23]. On the other hand, it has been demonstrated that TLR2 and TLR4 can activate the PI3K/Akt pathway through the Ras-related C3 botulinum toxin substrate 1 (Rac1), a member of the Rho family of GTPases [23]. Complimentarily, the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) (JAK/STAT) pathway is known to respond to a variety of PAMPs/DAMPs and cytokines, including different interleukins and INF-β. Relevantly, different studies have demonstrated that several members of the TLR family can phosphorylate different STAT members, suggesting a direct modulation of the JAK/STAT pathway [24, 25]. As is possible to observe, the molecular cascades that could be triggered secondarily to TLR activation are related with critical cellular processes including cell cycle modulation, apoptosis, and cytoskeleton remodeling, among others. This situation depicts the complexity of the immune response and the relevance of its modulation in the context of different

pathologies including neurodegenerative ones, such as AD and PD.

**4. Alzheimer's and Parkinson's diseases: Aβ/SNCA and TLRs**

neuronal loss, and neuronal circuitry breakdown [26, 27].

AD constitutes the main form of dementia in the elderly population. Although, AD is recognized by the memory impairment and the reduced cognitive performance, the clinical scenario starts with mood alterations at the very beginning of the disease followed by the compromise of the short-term memory and the loss of long-term memory as the pathology progresses. Histologically, AD is characterized by the atrophy of the frontal cortex, limbic area, and hippocampus. On the other hand, the molecular hallmarks of AD are the formation of the amyloid-β (Aβ) plaques, constituted by the aggregated forms of the amyloid-β peptide, and the intraneuronal formation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein [26]. Relevantly, beyond these hallmarks, AD also exhibits increased oxidative stress, mitochondrial dysfunction, and chronic inflammatory response. Altogether, these molecular alterations will lead to synaptic damage,

Relevantly, even when genetic conditions can lead to an early onset AD presentation, this accounts only for a small number of cases worldwide, with over 95% of the cases being termed as sporadic or late-onset AD. In this latter case, age and lifestyle have been defined as the main risk factors associated with the appearance of the disease [26, 27]. In agreement with the amyloid hypothesis of AD, these risk factors have a direct impact on the levels of Aβ leading to its increased production and subsequent accumulation within the brain [28, 29]. In this regard, different studies have linked the synaptic failure, mitochondrial dysfunction, tau hyperphosphorylation, glial activation, and neuronal death with increased levels of Aβ [27, 30]. Importantly, in the context of neuroinflammation, the ability of Aβ to induce the inflammatory response through the TLR2, TLR4, and TLR6, as well as their co-receptors including CD36, CD14, and CD47 has been widely demonstrated

**86**

PD corresponds to the second most common neurodegenerative disorder. PD is characterized by dopaminergic circuitry impairment caused by the loss of the dopaminergic neurons, mainly at the substantia nigra pars compacta (SNpc). Defined as synucleinopathy, PD exhibits neuronal inclusions of aggregated α-synuclein (SNCA) protein which can be located at the cell soma and/or neurites, forming the Lewy bodies and Lewy neurites [39]. SNCA plays relevant roles in the synaptic activity as it is linked with the recycling of synaptic vesicle pools [40–42]. Moreover, SNCA interferes with the dopamine metabolism affecting both the tyrosine hydroxylase, the enzyme in charge of synthetizing dopamine, and the dopamine transporter (DAT) [43, 44]. Similar to AD, even when the main signs of PD are associated with motor impairment, the pathological scenario begins much earlier with sleep disturbances and loss of olfaction which often passes unadvised to the patients or their relatives. Dementia is also an additional feature of the pathology and the affectation of memory can be part of the clinical picture. Although SNCA aggregation explains the damage to the dopaminergic neurons, the mechanisms behind SNCA dynamics have remained elusive [39, 45, 46]. Although PD can also emerge as a genetics-related disease with several genes linked to an early presentation, only a small proportion of the cases share this condition worldwide [39, 47]. In the same way, the vast majority of PD cases are linked to aging and lifestyle with the exposure of the patients to chemical xenobiotics, such as pesticides and recreational drugs being of most relevance [48]. Importantly, the SNCA aggregation is also related to the additional features observed during the pathological process, including mitochondrial dysfunction, increased oxidative stress, and neuroinflammation. Moreover, oxidative stress plays a central role in the pathophysiology of PD and the contribution of the ROS to the inflammatory milieu seems to be part of the establishment and progression of the disease.

Regarding the SNCA and inflammatory triggering, different researchers have demonstrated that depending on the aggregation status of SNCA, this protein can activate the TLRs, at least TLR2 and TLR4 [49–52]. Moreover, SNCA can be incorporated by the surrounding cells, particularly astrocytes, leading to the formation of SNCA inclusions also in these latter cells and helping to spread the SNCA pathology across the brain [53, 54]. Relevantly, PD can also be influenced by the systemic inflammatory status. Indeed, it has been recently demonstrated that increased levels of inflammatory mediators favor SNCA aggregation [55, 56].
