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Microglia-mediated T cell Infiltration Drives Neurodegeneration in Tauopathy

ABSTRACT: Extracellular 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 remain elusive. 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. We systematically compared the immunological milieus in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. We 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-1signaling both significantly ameliorated brain atrophy. Our 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE221856 | GEO | 2023/03/01

REPOSITORIES: GEO

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Project description:Alzheimer’s Disease (AD) is the most common cause of age-related dementia and the sixth leading cause of death in the United States. AD neuropathology is primarily characterized by the accumulation of extracellular beta-amyloid (Aβ) plaques and intraneuronal neurofibrillary tau tangles. In addition to these hallmark AD pathologies, many other important pathological changes occur in the brains of AD patients, including synaptic and neuronal loss and neuroinflammation. Most recently, genome-wide association studies (GWAS) have provided substantial new evidence that immune dysfunction may contribute to the development and progression of AD. To date over 60 GWAS loci have been identified and almost two thirds of these genes are highly expressed in microglia, the resident innate immune cell of the brain. These genetic discoveries have in turn inspired many new studies of microglial biology and the role of these cells in AD. In contrast, the role of the adaptive immunity in AD remains understudied, despite evidence that many of AD risk genes are also highly expressed in T and B cells. To investigate the role of T cell infiltration in AD, we examined T cells from immune-deficient AD mice via bone marrow transplantation studies using flow cytometry and immunohistochemistry; and from immune-intact transgenic AD model mice using flow cytometry, immunohistochemistry, and single-cell RNA sequencing. Our experiments demonstrate that multiple T cell subtypes infiltrate the AD brain, and that effector memory CD8 T cells are specifically enriched in response to Aβ pathology or a combination of Aβ and tau pathologies. Single-cell sequencing analysis revealed high expression of over 40 AD risk genes between several T cell sub-populations, implying a need for more research of these T cell phenotypes in AD development. Additionally, T-cell receptor (TCR) sequencing revealed increased clonal expansion of T cells from mice that developed Aβ pathology or Aβ and tau pathology, suggesting amyloid-driven recruitment and clonal expansion of T cells in these mice. Ultimately, this study demonstrates the crucial importance of investigating the role of T cells in AD and provides a guide for future experiments to continue to enhance our understanding of AD immunology.

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Microglia-mediated T cell Infiltration Drives Neurodegeneration in Tauopathy

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