期刊
NATURE
卷 552, 期 7685, 页码 355-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature25158
关键词
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资金
- Deutsche Forschungsgemeinschaft through Cluster of Excellence Immunosensation
- Clinical Research Group [KFO177]
- ERC InflammAct
- ERC PLAT-IL-1
- ERA-NET consortium TracInflam
- JPND consortium InCure
- [SFB670]
- [WA1477/6]
The spreading of pathology within and between brain areas is a hallmark of neurodegenerative disorders. In patients with Alzheimer's disease, deposition of amyloid-beta is accompanied by activation of the innate immune system and involves inflammasome-dependent formation of ASC specks in microglia. ASC specks released by microglia bind rapidly to amyloid-beta and increase the formation of amyloid-beta oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid-beta pathology. Here we show that intrahippocampal injection of ASC specks resulted in spreading of amyloid-beta pathology in transgenic double-mutant APP(Swe)PSEN1(dE9) mice. By contrast, homogenates from brains of APP(Swe)PSEN1(dE9) mice failed to induce seeding and spreading of amyloid-beta pathology in ASC-deficient APP(Swe)PSEN1(dE9) mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid-beta pathology in APP(Swe)PSEN1(dE9) mice. These findings support the concept that inflammasome activation is connected to seeding and spreading of amyloid-beta pathology in patients with Alzheimer's disease.
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