DOI: 10.1002/alz.082506 ISSN: 1552-5260

ApoE and immune system in the pathogenesis of tau‐mediated neurodegeneration

Xiaoying Chen
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology

Abstract

Background

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 and their interaction with innate immune response in the presence of Aβ or tau pathology.

Method

We systematically compared the immunological milieus in the brain with amyloid deposition or tau aggregation and neurodegeneration.

Models

Three AD mouse models, including Aβ models with amyloid deposition in both parenchyma and along the vessels and tau pathology models; as well as human brain samples with different Braak scores.

Result

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.

Conclusion

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.

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