Impact Of Trem2(R)(47)(H) Variant On Tau Pathology-Induced Gliosis And Neurodegeneration

Alzheimer's disease (AD) is characterized by plaques containing amyloid-f3 (Ap) and neurofibrillary tangles composed of aggregated, hyperphosphorylated tau. Beyond tau and Ali, evidence suggests that microglia play an important role in AD pathogenesis. Rare variants in the microglia-expressed triggering receptor expressed on myeloid cells 2 (TREM2) gene increase AD risk 2- to 4-fold. It is likely that these TR EM2 variants increase AD risk by decreasing the response of microglia to A beta and its local toxicity. However, neocortical A beta pathology occurs many years before neocortical tau pathology in AD. Thus, it will be important to understand the role of TREM2 in the context of tauopathy. We investigated the impact of the AD-associated TREM2 variant (R47H) on tau-mediated neuropathology in the PS19 mouse model of tauopathy. We assessed P519 mice expressing human TREM2(CV) (common variant) or human TREM2(R)(47)(H). P519-TREM2(R)(47)(H) mice had significantly attenuated brain atrophy and synapse loss versus PS19-TREM2(CV) mice. Gene expression analyses and CDR immunostaining revealed attenuated microglial reactivity in P519-TREM2(R)(47)(H) versus PS19-TREM2(CV) mice. There was also a decrease in phagocytosis of postsynaptic elements by microglia expressing TREM2(R)(47)(H )in the PS19 mice and in human AD brains. These findings suggest that impaired TREM2 signaling reduces microglia-mediated neurodegeneration in the setting of tauopathy.