Aging exacerbates the brain inflammatory micro-environment contributing to α-synuclein pathology and functional deficits in a mouse model of DLB/PD

Background: Although alpha-synuclein (alpha-syn) spreading in age-related neurodegenerative diseases such as Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) has been extensively investigated, the role of aging in the manifestation of disease remains unclear. Methods: We explored the role of aging and inflammation in the pathogenesis of synucleinopathies in a mouse model of DLB/PD initiated by intrastriatal injection of alpha-syn preformed fibrils (pff). Results: We found that aged mice showed more extensive accumulation of alpha-syn in selected brain regions and behavioral deficits that were associated with greater infiltration of T cells and microgliosis. Microglial inflammatory gene expression induced by alpha-syn-pff injection in young mice had hallmarks of aged microglia, indicating that enhanced age-associated pathologies may result from inflammatory synergy between aging and the effects of alpha-syn aggregation. Based on the transcriptomics analysis projected from Ingenuity Pathway Analysis, we found a network that included colony stimulating factor 2 (CSF2), LPS related genes, TNF alpha and poly rl:rC-RNA as common regulators. Conclusions: We propose that aging related inflammation (eg: CSF2) influences outcomes of pathological spreading of alpha-syn and suggest that targeting neuro-immune responses might be important in developing treatments for DLB/PD.

Automated summary

This study investigates the role of aging and inflammation in the manifestation of neurodegenerative diseases such as Parkinson's disease and dementia with Lewy bodies. The results show that aged mice have more extensive accumulation of alpha-synuclein and behavioral deficits compared to young mice. The study suggests that enhanced age-associated pathologies may result from inflammatory synergy between aging and the effects of alpha-synuclein aggregation.