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Microglia-derived ASC specks cross-seed amyloid-ß 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, Dietmar; Golenbock, Douglas T; Geyer, Matthias; Walter, Jochen; Latz, Eicke; Heneka, Michael T.
Nature; 552(7685): 355-361, 2017 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-29293211
The spreading of pathology within and between brain areas is a hallmark of neurodegenerative disorders. In patients with Alzheimer's disease, deposition of amyloid-ß 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-ß and increase the formation of amyloid-ß oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloidpathology. Here we show that intrahippocampal injection of ASC specks resulted in spreading of amyloidpathology in transgenic double-mutant APPSwePSEN1dE9 mice. By contrast, homogenates from brains of APPSwePSEN1dE9 mice failed to induce seeding and spreading of amyloidpathology in ASC-deficient APPSwePSEN1dE9 mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloidpathology in APPSwePSEN1dE9 mice. These findings support the concept that inflammasome activation is connected to seeding and spreading of amyloidpathology in patients with Alzheimer's disease.
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