Microglia‐mediated T cell Infiltration Drives Neurodegeneration in Tauopathy

Abstract

AbstractBackgroundExtracellular amyloid‐β (Aβ) deposition as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles (NFT) are two of the characteristic hallmarks in Alzheimer’s disease (AD). The regional progression of brain atrophy in AD highly correlates with tau accumulation but not amyloid deposition and the mechanisms of tau‐mediated neurodegeneration are not clear. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. To date, little is known about the extent or role of the adaptive immune response in the presence of Aβ or tau pathology.MethodWe utilized transgenic mice that develop Aβ deposition or tau pathology and neurodegeneration. We isolated all immune cells in the brain followed by single cell RNA sequencing and systematically compared the immunological milieus in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. Histological, biochemical, and behavioral analyses were also performed to assess the immune response and brain damage in the different mice with or without different treatments.ResultWe found that mice with tauopathy but not amyloid, developed a unique innate and adaptive immune response and that depletion of microglia or T‐cells blocked tau‐mediated neurodegeneration. T cells, especially cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the AD brain. T cell numbers correlated with the extent of neuronal loss, and dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of IFN‐γ and PD‐1 signaling both significantly ameliorated brain atrophy.ConclusionOur results thus reveal a tauopathy and neurodegeneration‐related immune hub involving activated microglia and T cell responses, which could serve as therapeutic targets for preventing neurodegeneration in AD and primary tauopathies.