Neuroinflammation and Alpha-Synuclein Oligomer Toxicity in the Pathogenesis of Lewy Body Dementia and Parkinson's Disease

La Vitola, Pietro (2020). Neuroinflammation and Alpha-Synuclein Oligomer Toxicity in the Pathogenesis of Lewy Body Dementia and Parkinson's Disease. PhD thesis The Open University.



Aggregated α-synuclein has emerged as the core constituent of the typical neuronal inclusions found in Parkinson’s disease and Lewy body dementia. Therefore, huge efforts have been made to unveil the mechanisms underlying α-syn toxicity. Accumulating evidence suggests extracellular α-synuclein oligomers (α-synOs) as potential culprits involved in the neurodegenerative process. To elucidate the pathways mediating α-synO non-cell- autonomous actions, several mechanisms including uncontrolled neuroinflammatory responses and protein-protein interactions have been put forward.

Through an acute model based on the intracerebroventricular (ICV) injection of α-synuclein monomers, oligomers or fibrils in C57BL/6N mice we demonstrate that only α-synOs impair memory establishment in association with glial activation. Furthermore, our findings identify neuroinflammation as a driving force of α-synO detrimental action on memory, and the involvement of the Toll-like receptor 2. Based on recent data depicting the cellular prion protein (PrPC) as an α-synO interactor, we have further investigated its role in fostering α- synO harmful activities. We found that PrPC does not mediate α-synO toxicity in vitro or α- synO-induced memory deficiency in vivo. In fact, PrPC knock-out mice ICV injected with α-synOs display both memory impairment and gliosis. Consistently, our in vitro biochemical studies do not reveal any direct PrPC-α-synO binding.

To evaluate the influence of neuroinflammation on PD pathogenesis, we have developed a “double-hit” approach. Using an acute mouse model based on the peripheral administration of lipopolysaccharide (LPS) and subsequent ICV injection of α-synOs at an inactive dose, we demonstrate that the LPS induces a long-lasting neuroinflammatory response enhancing α-synO actions. Moreover, we show that the LPS peripheral administration worsens cognitive deficits even in an A53T PD mouse model. Altogether, by identifying neuroinflammation as an α-synO-mediator and as a factor influencing the initiation/progressions of PD, we highlight it as a valuable research topic to identify potential targets for developing new therapeutic strategies.

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