Peripheral inflammation exacerbates α‐synuclein toxicity and neuropathology in Parkinson's models

Aims Parkinson’s disease and related disorders are devastating neurodegenerative pathologies. Since α‐synuclein was identified as a main component of Lewy bodies and neurites, efforts have been made to clarify the pathogenic mechanisms of α‐synuclein's detrimental effects. α‐synuclein oligomers are the most harmful species and may recruit and activate glial cells. Inflammation is emerging as a bridge between genetic susceptibility and environmental factors co‐fostering Parkinson’s disease. However, direct evidence linking inflammation to the harmful activities of α‐synuclein oligomers or to the Parkinson’s disease behavioural phenotype is lacking. Methods To clarify whether neuroinflammation influences Parkinson’s disease pathogenesis, we developed: (i) a ‘double‐hit’ approach in C57BL/6 naive mice where peripherally administered lipopolysaccharides were followed by intracerebroventricular injection of an inactive oligomer dose; (ii) a transgenic ‘double‐hit’ model where lipopolysaccharides were given to A53T α‐synuclein transgenic Parkinson’s disease mice. Results Lipopolysaccharides induced a long‐lasting neuroinflammatory response which facilitated the detrimental cognitive activities of oligomers. LPS‐activated microglia and astrocytes responded differently to the oligomers with microglia activating further and acquiring a pro‐inflammatory M1 phenotype, while astrocytes atrophied. In the transgenic ‘double‐hit’ A53T mouse model, lipopolysaccharides aggravated cognitive deficits and increased microgliosis. Again, astrocytes responded differently to the double challenge. These findings indicate that peripherally induced neuroinflammation potentiates the α‐synuclein oligomer’s actions and aggravates cognitive deficits in A53T mice. Conclusions The fine management of both peripheral and central inflammation may offer a promising therapeutic approach to prevent or slow down some behavioural aspects in α‐synucleinopathies.