Abstract Body

ɑ-synuclein (ɑ-syn) progressively accumulates in age related neurodegenerative diseases such as Alzheimer’s Disease (AD), Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB). Although ɑ-syn aggregation and spreading has been extensively investigated, the role of immune dysregulation in the manifestation of disease needs to considered. Identification of selective immune related pathways in synucleinopathies of the ageing population might be crucial in terms of developing new therapeutics. Relevant to the innate immune system, we have identified several immune receptors that mediate neuroinflammation in synucleinopathies, such as Toll-like receptor 2 (TLR2). Upon activation by extracellular ɑ-syn and aged mediated factors TLR’s signal in microglial cells via LRRK2 to NFATc2 leading to neuroinflammation and neurodegeneration. Therapeutical targets of this pathway involve using immunotherapies selectively binding to specific ɑ-syn species and TLR2 as well as small molecule inhibitors of TLR’s, LRKK2 and NFAT’s. In terms of adaptive immunity, we have identified different populations of T cells including CD4’s and NKT trafficking into the CNS mediating activation of microglia and neurodegeneration that can be targeted with antibodies binding to CD1d. Moreover, interceding the effects between extracellular ɑ-syn, aging and immune dysfunction we have identified a deregulation between CSF1 and CSF2 as an important mediator that might be amenable for therapeutic interventions including gene silencing. Together these studies suggest that targeting ɑ-syn and aging mediated neuro-immune responses might be an important adjuvant therapeutics for synucleinopathies.