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

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

doi:10.1038/nature25158

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

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Riedel, D.
Facility for Electron Microscopy, MPI for biophysical chemistry, Max Planck Society;

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Citation

Venegas, C., Kumar, S., Franklin, B. S., Dierkes, T., Brinkschulte, R., Tejera, D., et al. (2017). Microglia-derived ASC specks cross-seed amyloid-beta in Alzheimer's disease. Nature, 552(7685), 355-361. doi:10.1038/nature25158.

Cite as: https://hdl.handle.net/11858/00-001M-0000-002E-A451-A

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.