The spreading of pathology within and between brain areas is a hallmark of neurodegenerative disorders. In patients with Alzheimer's disease, deposition of amyloid-β 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-β and increase the formation of amyloid-β oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid-β pathology. Here we show that intrahippocampal injection of ASC specks resulted in spreading of amyloid-β pathology in transgenic double-mutant APPPSEN1 mice. By contrast, homogenates from brains of APPPSEN1 mice failed to induce seeding and spreading of amyloid-β pathology in ASC-deficient APPPSEN1 mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid-β pathology in APPPSEN1 mice. These findings support the concept that inflammasome activation is connected to seeding and spreading of amyloid-β pathology in patients with Alzheimer's disease.
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