Impacts of Plcg2 variants on adaptive immune cells in the late-onset Alzheimer’s disease (LOAD2) mouse model 9265

Abstract Description Alzheimer’s Disease (AD) is a leading cause of dementia, characterized by the formation of amyloid plaques and tau tangles, as well as neuroinflammation and myelin dysfunction. Recent genome-wide association studies have associated Plcg2 hypermorphic and hypomorphic polymorphisms with reduced (P522R) and increased (M28L and very rare loss-of-function variants) risk of developing AD, respectively. PLCγ2 regulates lipid metabolism and intracellular calcium, controlling multiple signaling pathways in a variety of cell types, including adaptive and innate immune cells. T cells influence myelin homeostasis during aging as well as the pathogenesis and progression of AD. PLCγ2 is expressed in early T cell progenitors, in mature regulatory T cells (Tregs) and in antigen presenting cells that direct T development and tolerance induction in the thymus and their maintenance in the periphery. These observations suggest that PLCγ2 may regulate T cell reactivity and tolerance in the brain, either by modulating clonal deletion or diversion of autoreactive T cells to the Treg lineage in the thymus, or by influencing the balance of effector (Teff) and Tregs in peripheral tissues. Preliminary analyses of Plcg2 knockout mice, as well as mice expressing knockin humanized Plcg2 P522R and M28L on a LOAD2 (hAβ, APOE4, Trem2R47H) background suggest a role for PLCγ2 in regulating frequencies of CD4 and CD8 Tregs and Tbet+CD11c+ B cells in lymphoid organs and brain. Funding Sources Supported by UT Health Microbiology, Immunology, and Molecular Genetics Departmental Pilot Project Topic Categories Neuroimmunology (NEUR)