T cell drives microglia specific metabolic plasticity and neurodegeneration in Alzheimer disease 4098

Description The regional progression of brain atrophy in Alzheimer’s disease highly correlates with tau accumulation. There are changes in adaptive immunity in AD and the increases in activated CD8+ T cells in the brain correlate with tau pathology. Further, there is a dynamic transformation of the CD8+ T cell cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Depletion of brain-resident microglia, infiltrated T cells, as well as, inhibiting IFN-γ signaling all significantly ameliorated brain atrophy. To date, little is known about the interaction between T cells and brain resident microglia. Here we use APOE isoforms-dependent mouse models and human neuroimmune axis models to show that microglia coordinate immune modulatory response against immune challenges in AD. Adaptive immune deficiency had strongly decreased microglial reactivity and microglia-mediated synaptic engulfment in tauopathy. Adaptive Immune deficiency ameliorates Tau-linked glial lipid accumulation. Of note, using large-scale transcriptome and chromatin profiling, we show that T cell shape microglia-specific metabolic plasticity in both genetic and epigenetic resolution. Our results thus reveal a tauopathy and neurodegeneration-related immune hub involving activated microglia and T cell responses, which could potentially serve as therapeutic targets for preventing neurodegeneration in AD and primary tauopathies. Funding Sources This research was supported by Cure Alzheimer’s Foundation and Alzheimer’s Association Foundation. Topic Categories Neuroimmunology (NEUR)