Microglia-derived ASC specks cross-seed amyloid-beta in Alzheimer's disease

Venegas, Carmen; Kumar, Sathish; Franklin, Bernardo S.; Dierkes, Tobias; Brinkschulte, Rebecca; Tejera, Dario; Vieira-Saecker, Ana; Schwartz, Stephanie; Santarelli, Francesco; Kummer, Markus P.; Griep, Angelika; Gelpi, Ellen; Beilharz, Michael; Riedel, Die

Publicación: NATURE
VL / 552 - BP / 355 - EP / +
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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