Impact of [TREM2.sup.R47H] variant on tau pathology--induced gliosis and neurodegeneration

Alzheimer's disease (AD) is characterized by plaques containing amyloid-[beta] (Ap) and neurofibrillary tangles composed of aggregated, hyperphosphorylated tau. Beyond tau and A[beta], 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 TREM2 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 PS19 mice expressing human [TREM2.sup.CV] (common variant) or human [TREM2.sup.R47H]. [PS19-TREM2.sup.R47H] mice had significantly attenuated brain atrophy and synapse loss versus [PS19-TREM2.sup.CV] mice. Gene expression analyses and CD68 immunostaining revealed attenuated microglial reactivity in [PS19-TREM2.sup.R47H] versus [PS19-TREM2.sup.CV] mice. There was also a decrease in phagocytosis of postsynaptic elements by microglia expressing [TREM2.sup.R47H] 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.
Introduction Alzheimer's disease (AD) is the leading cause of dementia worldwide and is the sixth leading cause of death in the United States (1). The histopathological hallmarks of AD are [...]