Immune and inflammatory interactions in Alzheimer's disease-related dementias

National Institute On Aging

Investigators

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Abstract

Using inter-laboratory funding we established the a-synuclein pre-formed fibril (PFF) injection model in the NIA/IRP and used it to evaluate the effect of age in the development of neuropathology, behavioral defects and the role of adaptive immunity. Additionally, we evaluated the status of microglial inflammation during disease progression. For this we injected PFF intra-striatally in matched cohorts of young and old mice obtained from the NIA aging colony and assayed the above characteristics at 1 and 3 months post-injection. These studies were published last year. During FY23 we accomplished the following: We continued investigating the role of chronic systemic low grade inflammation on Ab plaque pathology, gene expression and behavioral outcomes in the 5xFAD mouse model of Alzheimer's disease (AD). Chronic inflammation was induced by treatment of mice with sub-acute doses of dextran sodium sulfate (DSS) over 3 months. Physiological parameters were measured throughout treatment, behavioral tests were carried out in the last two weeks and tissues were harvested for gene expression studies and neuropathology at the end of 3 months. Flow cytometric studies of immune cell populations in the brain were performed at the end of the study. These studies were carried with female 5xFAD mice and age-matched non-transgenic controls. Microglial RNA was subject to RNA-seq. Preliminary analyses indicate that changes induced by pathogenic transgenes are exaggerated by DSS-induced chronic inflammation, suggesting a plausible mechanism for age-associated development of AD. To rigorously confirm these results and to harvest tissue for histopathology the entire experimental plan was repeated during the current fiscal year. To determine the extent to which low grade DSS treatment recapitulated features of age associated chronic inflammation, we compared gene expression profiles in liver from young/old mice to young mice treated with DSS. We found that 1) effects of DSS and aging were much more pronounced in male mice and 2) that similarities with age in both males and females was at the the level of inflammation and associated pathways. These results compelled us to revisit the effects of DSS in male 5xFAD mice mice. This experiment will be completed in mid-October after which tissues will be processed for RNA-Seq, immunohistochemistry and flow cytometry.