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

Although ɑ-synuclein (ɑ-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. We explored the role of aging and inflammat...

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Published in:	Molecular neurodegeneration 2022-09, Vol.17 (1), p.60-60, Article 60
Main Authors:	Iba, Michiyo, McDevitt, Ross A, Kim, Changyoun, Roy, Roshni, Sarantopoulou, Dimitra, Tommer, Ella, Siegars, Byron, Sallin, Michelle, Kwon, Somin, Sen, Jyoti Misra, Sen, Ranjan, Masliah, Eliezer
Format:	Article
Language:	eng
Subjects:	Aging alpha-Synuclein - metabolism Alzheimers disease Animals Brain - metabolism Colony-stimulating factor Dementia Dementia disorders Dementia with Lewy bodies Disease Models, Animal Experiments Fibrils Gene expression Inflammation Inflammation - metabolism Injection Lewy bodies Lipopolysaccharides Lymphocytes T Mice Microglia Movement disorders Neurodegeneration Neurodegenerative diseases Parkinson Disease - metabolism Parkinson's disease Parkinsons disease Pathology Preformed fibrils Proteins Surgery Synuclein Synucleinopathies Transcriptomics ɑ-synuclein
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Summary:	Although ɑ-synuclein (ɑ-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. 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 ɑ-syn preformed fibrils (pff). We found that aged mice showed more extensive accumulation of ɑ-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 ɑ-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 ɑ-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, TNFɑ and poly rl:rC-RNA as common regulators. We propose that aging related inflammation (eg: CSF2) influences outcomes of pathological spreading of ɑ-syn and suggest that targeting neuro-immune responses might be important in developing treatments for DLB/PD.
ISSN:	1750-1326 1750-1326