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

Venegas, C; Kumar, S; Franklin, BS; Dierkes, T; Brinkschulte, R; Tejera, D; Vieira-Saecker, A; Schwartz, S; Santarelli, F; Kummer, MP; Griep, A; Gelpi, E; Beilharz, M; Riedel, D; Golenbock, DT; Geyer, M; Walter, J; Latz, E; Heneka, MT

NATURE
2017
VL / 552 - BP / 355 - EP / +
abstract
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.
197th Global

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PROYECTO FINANCIADO POR PLAN NACIONAL DE INVESTIGACIÓN AGENCIA ESTATAL DE INVESTIGACIÓN, MINISTERIO DE CIENCIA E INNOVACIÓN. PID2019-109127RB-I00