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Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy

Nature (London), 2023-03, Vol.615 (7953), p.668-677 [Peer Reviewed Journal]

2023. The Author(s), under exclusive licence to Springer Nature Limited. ;Copyright Nature Publishing Group Mar 23, 2023 ;ISSN: 0028-0836 ;EISSN: 1476-4687 ;DOI: 10.1038/s41586-023-05788-0 ;PMID: 36890231

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Title:
Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy
Author: Chen, Xiaoying ; Firulyova, Maria ; Manis, Melissa ; Herz, Jasmin ; Smirnov, Igor ; Aladyeva, Ekaterina ; Wang, Chanung ; Bao, Xin ; Finn, Mary Beth ; Hu, Hao ; Shchukina, Irina ; Kim, Min Woo ; Yuede, Carla M ; Kipnis, Jonathan ; Artyomov, Maxim N ; Ulrich, Jason D ; Holtzman, David M
Subjects: Accumulation ; Adaptive immunity ; Alzheimer Disease - immunology ; Alzheimer Disease - metabolism ; Alzheimer Disease - pathology ; Alzheimer's disease ; Amyloid beta-Peptides - immunology ; Amyloid beta-Peptides - metabolism ; Animals ; Atrophy ; Brain ; Brain - immunology ; Brain - metabolism ; Brain - pathology ; Clone Cells - immunology ; Clone Cells - metabolism ; Clone Cells - pathology ; Cytotoxicity ; Dendritic cells ; Depletion ; Deposition ; Immune response ; Immune system ; Immunity, Innate ; Immunology ; Innate immunity ; Lymphocytes ; Lymphocytes T ; Mice ; Microglia ; Microglia - immunology ; Microglia - metabolism ; Neurodegeneration ; Neurodegenerative diseases ; Neurofibrillary tangles ; Neurofibrillary Tangles - immunology ; Neurofibrillary Tangles - metabolism ; Neurofibrillary Tangles - pathology ; Pathology ; Plaque, Amyloid - immunology ; Plaque, Amyloid - metabolism ; Plaque, Amyloid - pathology ; Receptors, Antigen, T-Cell - immunology ; Receptors, Antigen, T-Cell - metabolism ; Senile plaques ; Signal transduction ; T-Lymphocytes - immunology ; T-Lymphocytes - metabolism ; T-Lymphocytes - pathology ; T-Lymphocytes, Cytotoxic - immunology ; T-Lymphocytes, Cytotoxic - metabolism ; T-Lymphocytes, Cytotoxic - pathology ; Tau protein ; tau Proteins - immunology ; tau Proteins - metabolism ; Tauopathies - immunology ; Tauopathies - metabolism ; Tauopathies - pathology ; Therapeutic targets
Is Part Of: Nature (London), 2023-03, Vol.615 (7953), p.668-677
Description: 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 disease . The regional progression of brain atrophy in Alzheimer's disease 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. 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 pathology . 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.
Publisher: England: Nature Publishing Group
Language: English
Identifier: ISSN: 0028-0836
EISSN: 1476-4687
DOI: 10.1038/s41586-023-05788-0
PMID: 36890231
Source: ProQuest One Psychology
AUTh Library subscriptions: ProQuest Central
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Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy

2023. The Author(s), under exclusive licence to Springer Nature Limited. ;Copyright Nature Publishing Group Mar 23, 2023 ;ISSN: 0028-0836 ;EISSN: 1476-4687 ;DOI: 10.1038/s41586-023-05788-0 ;PMID: 36890231

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