The effect of APOE isoforms on the immune response and tau-mediate neurodegeneration 2135

Abstract Description Alzheimer’s disease (AD) is a neurodegenerative disorder marked by amyloid-β deposits and tau aggregation. The apolipoprotein E (APOE) gene is the strongest risk factor for late-onset AD, with APOE4 increasing and APOE2 reducing the risk compared to APOE3. Notably, the absence of APOE is strongly protective against tau or amyloid pathology in mouse models. Increased brain infiltrating T cells interacting with reactive microglia contribute to tau-mediated neurodegeneration in P301S Tau transgenic mice, while T cell depletion provides significant neuroprotection. However, the role of APOE isoforms in immune response during neurodegeneration remains unknown. Here, we investigated whether APOE isoform and expression influenced the T cell response in P301S mice expressing different APOE isoforms (APOE2, APOE3, APOE4) or lacking APOE (APOE KO). Isolated leukocytes from mouse brains were analyzed using scRNA-seq to determine immune cell populations influenced by tauopathy and APOE isoforms. We found that APOE isoforms significantly affect the severity of tauopathy (APOE4 > APOE3 = APOE2 >> APOE KO). The highest microglial and astrocyte reactivity occurred with APOE4. scRNA-seq revealed increased IFN-responsive T cells in tauopathy brains, with distinct signatures on exhausted T cells linked to APOE isoforms. This research highlights how APOE isoforms shape innate and adaptive immune responses in tauopathy. Funding Sources This work was funded by the National Institutes of Health grants RF1NS090934 (D.M.H.), NIH 1U19AG069701 (D.M.H.), the JPB Foundation (D.M.H.), the Tau Consortium (D.M.H), and the Cure Alzheimer’s Fund (D.M.H). Topic Categories Neuroimmunology (NEUR)