Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy

Xiaoying Chen, Maria Firulyova, Melissa Manis, Jasmin Herz, Igor Smirnov, Ekaterina Aladyeva, Chanung Wang, Xin Bao, Mary Beth Finn, Hao Hu, Irina Shchukina, Min Woo Kim, Carla M. Yuede, Jonathan Kipnis, Maxim N. Artyomov, Jason D. Ulrich and David M. Holtzman ()
Additional contact information
Xiaoying Chen: Washington University School of Medicine
Maria Firulyova: Almazov National Medical Research Centre
Melissa Manis: Washington University School of Medicine
Jasmin Herz: Washington University School of Medicine
Igor Smirnov: Washington University School of Medicine
Ekaterina Aladyeva: Washington University School of Medicine
Chanung Wang: Washington University School of Medicine
Xin Bao: Washington University School of Medicine
Mary Beth Finn: Washington University School of Medicine
Hao Hu: Washington University School of Medicine
Irina Shchukina: Washington University School of Medicine
Min Woo Kim: Washington University School of Medicine
Carla M. Yuede: Washington University School of Medicine
Jonathan Kipnis: Washington University School of Medicine
Maxim N. Artyomov: Washington University School of Medicine
Jason D. Ulrich: Washington University School of Medicine
David M. Holtzman: Washington University School of Medicine

Nature, 2023, vol. 615, issue 7953, 668-677

Abstract: Abstract Extracellular deposition of amyloid-β as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles are two of the characteristic hallmarks of Alzheimer’s disease1,2. The regional progression of brain atrophy in Alzheimer’s disease highly correlates with tau accumulation but not amyloid deposition3–5, 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. So far, little is known about the extent or role of the adaptive immune response and its interaction with the innate immune response in the presence of amyloid-β or tau pathology6. Here we systematically compared the immunological milieux in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. We found that mice with tauopathy but not those with amyloid deposition developed a unique innate and adaptive immune response and that depletion of microglia or T cells blocked tau-mediated neurodegeneration. Numbers of T cells, especially those of cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the Alzheimer’s disease brain. T cell numbers correlated with the extent of neuronal loss, and the cells dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of interferon-γ and PDCD1 signalling 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 Alzheimer’s disease and primary tauopathies.

Date: 2023
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DOI: 10.1038/s41586-023-05788-0

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