Presenting Author: Alexis M Johnson
, Graduate Student at Univ. of Virginia
Abstract:
Tauopathies, including Alzheimer's disease (AD) and frontotemporal dementia, are marked by hyperphosphorylated-tau aggregates that escalate in severity in the presence of robust neuroinflammation. Despite this recognized link, the intracellular signaling mechanisms propelling neurotoxic microglia activation remain poorly defined. GWAS implicate immunotyrosine activating and inhibitory motif-containing receptors in AD. These receptors have been extensively studied in Aβ-driven AD models, and their downstream signaling effectors, SYK and CARD9, have been described by our lab to possess beneficial roles in orchestrating microglial activation in response to Aβ plaques. This study explores the role of microglial SYK in tau-mediated neurodegeneration and its dependence on CARD9 signaling. We utilized two mouse models: PS19 Sykfl/fl Cx3cr1Ert2Cre and PS19 CARD9-/- mice. Our findings reveal that microglial Syk deletion protects against learning deficits and tauopathy when compared to PS19 SykWT littermate controls. PS19 SykKO microglia maintained a homeostatic phenotype and failed to upregulate markers of activation. However, the rescue of cognition, tau burden, and microgliosis does not phenocopy in PS19 CARD9-/- mice, showing no discernible differences from PS19 CARD9+/+ mice. These results suggest microglial SYK signaling antagonizes tauopathy independent of CARD9. Moreover, suppressing microglial SYK signaling may offer a novel therapeutic strategy to treat tauopathies.