Details

Autor(en) / Beteiligte

• 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.

Titel

Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease

Ist Teil von

• Nature (London), 2017-12, Vol.552 (7685), p.355-361

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2017

Beschreibungen/Notizen

• 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 APP Swe PSEN1 dE9 mice. By contrast, homogenates from brains of APP Swe PSEN1 dE9 mice failed to induce seeding and spreading of amyloid-β pathology in ASC-deficient APP Swe PSEN1 dE9 mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid-β pathology in APP Swe PSEN1 dE9 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. Deposition and spreading of amyloid-β pathology in mice requires binding to microglia-released ASC specks. ASC specks bind to amyloid-β Innate immune activation in Alzheimer's disease involves the inflammasome-dependent formation of specks of adapter protein ASC (an apoptosis-associated speck-like protein containing a caspase recruitment domain) in microglial cells. Here it is shown that ASC specks released by microglia bind to amyloid-β and increase amyloid-β oligomer and aggregate formation, acting as an inflammation-driven cross-seed for amyloid-β pathology.