期刊
SCIENCE ADVANCES
卷 7, 期 43, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abg4980
关键词
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资金
- Alzheimer's Research U.K. [ARUK-RF2017A-4]
- European Union (EU/EFPIA/Innovative Medicines Initiative 2, Joint Undertaking) [116060]
- Wellcome Trust [206248/Z/17/Z]
- Royal Society [206248/Z/17/Z]
- UKDRI (U.K. Medical Research Council)
- UKDRI (Alzheimer's Society)
- UKDRI (Alzheimer's Research UK)
- iCase BBSRC
- Eli Lilly [G103374]
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine
- NIH [P30-AG010133]
- National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre
- Alzheimer's Society
- Wellcome Trust [206248/Z/17/Z] Funding Source: Wellcome Trust
The study reveals that tau protein aggregation in neurons can trigger inflammation and cellular senescence in microglia, leading to impaired phagocytic function and release of tau aggregates. This process facilitates the spreading of tau protein, indicating a potential mechanism for neurodegenerative diseases.
The microtubule-associated protein tau aggregates in multiple neurodegenerative diseases, causing inflammation and changing the inflammatory signature of microglia by unknown mechanisms. We have shown that microglia phagocytose live neurons containing tau aggregates cultured from P301S tau mice due to neuronal tau aggregateinduced exposure of the eat me signal phosphatidylserine. Here, we show that after phagocytosing tau aggregatebearing neurons, microglia become hypophagocytic while releasing seed-competent insoluble tau aggregates. These microglia express a senescence-like phenotype, demonstrated by acidic beta-galactosidase activity, secretion of paracrine senescence-associated cytokines, and maturation of matrix remodeling enzymes, results that are corroborated in P301S mouse brains and ex vivo brain slices. In particular, the nuclear factor kappa B-dependent activation of matrix metalloprotease 3 (MMP3/stromelysin1) was replicated in brains from patients with tauopathy.These data show that microglia that have been activated to ingest live tau aggregates-bearing neurons behave hormetically, becoming hypofunctional while acting as vectors of tau aggregate spreading.
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