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

National Institute On Aging

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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. During FY22 we accomplished the following: 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 -syn preformed fibrils (pff). We found that aged mice showed more extensive accumulation of -syn and behavioral deficits that was associated with greater infiltration of T cells and microgliosis. Microglial inflammatory gene expression induced by -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 -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 and poly rl:rC-RNA as common regulators. We propose that aging related inflammation (eg: CSF2) influences outcomes of pathological spreading of -syn and suggest that targeting neuro-immune responses might be important in developing treatments for DLB/PD. These studies were accepted for publication in Molecular Neurodegeneration. We investigated the role of chronic systemic low grad inflammation on Ab plaque pathology, gene expression and behavioral outcomes in the 5xFAD mouse model of Alzheimers disease. 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. Data analyses are ongoing.