Peripheral inflammation influences α‐synuclein toxicity and neuropathology in Parkinson’s disease models

Background Parkinson’s disease (PD) and its related disorders, including Lewy body dementia, are devastating progressive neurodegenerative pathologies arising from the interaction between environmental factors and genetic susceptibility. Since the discovery of α‐synuclein as the main constituent of Lewy bodies and neurites, and the identification of mutations in the gene encoding for the protein in familial form of PD, numerous efforts have been made to clarify the pathogenic role played by α‐synuclein. Oligomeric assemblies of α‐synuclein, originating from its aberrant aggregation, represent the most harmful species. Besides direct action on neurons, α‐synuclein oligomers may act through non‐cell‐autonomous pathways involving chronic and/or dysregulated activation of glial cells. Initially considered as a mere secondary phenomenon, inflammation is now viewed as the bridge between genetic susceptibility and environmental factors co‐fostering PD. Method To get direct insight on the role of neuroinflammation in influencing PD pathogenesis, we have developed a “double‐hit” in vivo approach, based on the peripheral administration of lipopolysaccharides (LPS) to C57 naïve mice, followed, one month later, by the intracerebroventricular injection of low dose of α‐synuclein oligomers characterized by atomic force microscopy. LPS was also injected to a‐synuclein A53T transgenic mice, motor and cognitive behavior was analyzed together with histopathological examinations in both models. Result LPS induced a long‐lasting inflammatory response in the CNS, facilitating the detrimental activities of α‐synuclein oligomers: memory deficits and histopathological alterations. LPS‐activated microglia and astrocytes respond differently to the oligomers, with microglia further activated and acquiring a proinflammatory M1 phenotype, and astrocytes appearing atrophic. In addition, the peripheral administration of LPS in the A53T transgenic PD mouse model aggravated cognitive deficits, together with an increased microgliosis. Again, astrocytes responded differently from microglial cells to the double challenge presented by A53T genetic background and the treatment with LPS. Conclusion The peripherally‐induced neuroinflammation potentiates the α‐synuclein oligomer actions and aggravates cognitive deficits in A53T mice. The management of both peripheral and central inflammation may offer a promising therapeutic approach to prevent or slow down some pathological aspects in α‐synucleinopathies.