*3.2.2. TLRs and SNCA in PD*

Similar to Aβ, different research groups have shown that SNCA induces the inflammatory response through a TLR2- and TLR4-mediated mechanism, leading to TNF-α, IL-6 and CXCL1 expression via the MyD88-NF-kB pathway [78–80]. Interestingly, it has been demonstrated that while monomeric SNCA activates TLR2, the oligomeric forms tend to activate TLR4 [81]. Complimentarily, a relevant issue has emerged from recent research which has demonstrated that inflammation itself, through a caspase-mediated mechanism, can favour the aggregation of SNCA [51, 52]. This latter finding further support the idea of a self-sustained cycle which amplifies the initial damage exerted by the SNCA and contributes to the progression of the pathology. However, beyond the TLR-NF-kB axis and the production of pro-inflammatory mediators, additional aspects should be considered regarding SNCA hallmarks.

Within neurons, aggregated SNCA, whether in the soma or in neurites, will cause cell death with the subsequent release of cellular content, the components of which will release additional DAMPs capable of interacting with additional TLRs [82]. Moreover, it has been demonstrated that SNCA can be exocytosed actively from neurons, incorporated by the surrounding astrocytes, and then further aggregated, causing the formation of inclusion bodies within the new host cells [83]. Considering that the primary function of astrocytes is related to providing metabolic support to neurons and modulating the neurotransmitter metabolism within synapses, the SNCA pathology will not only involve the inflammatory response of astrocytes but will compromise its physiology, enhancing the neuronal network damage verified during PD pathophysiology [84–86]. On the other hand, although microglia will react to SNCA through TLRs, SNCA can also influence the activity of activated microglia against further pro-inflammatory signals, suggesting that SNCA can induce a priming effect on the microglia population, exerting a type of modulation on the strength of the inflammatory response [70, 87]. Thus, in the case of SNCA, this molecule can not only induce/perpetuate a pro-inflammatory status but also lead to an increased susceptibility to any inflammatory process.

### **3.3. Mitochondrial dysfunction**

An additional common feature of both pathologies is the increased production of ROS/ RNS. Indeed, an important end point of glial activation is that in response to the initial inflammatory trigger, Aβ in the case of AD and SNCA in PD, astrocytes and microglia will produce not only further inflammatory mediators, such as TNF-α and ILs, but also ROS/RNS [85]. The increased production of ROS and RNS will alter the surrounding microenvironment, and these species will be able to interact with the lipids of the plasma membrane, proteins and nucleic acids of the contiguous cells, ultimately affecting component of the neuronal circuitry, such 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.

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

Similar to Aβ, different research groups have shown that SNCA induces the inflammatory response through a TLR2- and TLR4-mediated mechanism, leading to TNF-α, IL-6 and CXCL1 expression via the MyD88-NF-kB pathway [78–80]. Interestingly, it has been demonstrated that while monomeric SNCA activates TLR2, the oligomeric forms tend to activate TLR4 [81]. Complimentarily, a relevant issue has emerged from recent research which has demonstrated that inflammation itself, through a caspase-mediated mechanism, can favour the aggregation of SNCA [51, 52]. This latter finding further support the idea of a self-sustained cycle which amplifies the initial damage exerted by the SNCA and contributes to the progression of the pathology. However, beyond the TLR-NF-kB axis and the production of pro-inflammatory

Within neurons, aggregated SNCA, whether in the soma or in neurites, will cause cell death with the subsequent release of cellular content, the components of which will release additional DAMPs capable of interacting with additional TLRs [82]. Moreover, it has been demonstrated that SNCA can be exocytosed actively from neurons, incorporated by the surrounding astrocytes, and then further aggregated, causing the formation of inclusion bodies within the new host cells [83]. Considering that the primary function of astrocytes is related to providing metabolic support to neurons and modulating the neurotransmitter metabolism within synapses, the SNCA pathology will not only involve the inflammatory response of astrocytes but will compromise its physiology, enhancing the neuronal network damage verified during PD pathophysiology [84–86]. On the other hand, although microglia will react to SNCA through TLRs, SNCA can also influence the activity of activated microglia against further pro-inflammatory signals, suggesting that SNCA can induce a priming effect on the microglia population, exerting a type of modulation on the strength of the inflammatory response [70, 87]. Thus, in the case of SNCA, this molecule can not only induce/perpetuate a pro-inflamma-

should be the appropriate approach to a TREM2-related intervention [76, 77].

mediators, additional aspects should be considered regarding SNCA hallmarks.

tory status but also lead to an increased susceptibility to any inflammatory process.

An additional common feature of both pathologies is the increased production of ROS/ RNS. Indeed, an important end point of glial activation is that in response to the initial inflammatory trigger, Aβ in the case of AD and SNCA in PD, astrocytes and microglia will produce not only further inflammatory mediators, such as TNF-α and ILs, but also ROS/RNS [85]. The increased production of ROS and RNS will alter the surrounding microenvironment, and these species will be able to interact with the lipids of the plasma membrane, proteins and nucleic acids of the contiguous cells, ultimately affecting component of the neuronal circuitry, such

*3.2.2. TLRs and SNCA in PD*

54 Recent Advances in Neurodegeneration

**3.3. Mitochondrial dysfunction**

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/ or progression of both diseases.
