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Nature. 2017 Dec 20;552(7685):355-361. doi: 10.1038/nature25158.

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

Author information

1
Department of Neurodegenerative Diseases and Gerontopsychiatry, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
2
Department of Neurology, University of Bonn, 53127 Bonn, Germany.
3
Institute of Innate Immunity, University of Bonn, 53127 Bonn, Germany.
4
Neurological Tissue Bank, University of Barcelona-Hospital Clinic, IDIBAPS, 08036 Barcelona, Spain.
5
Electron Microscopy Group, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
6
Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
7
Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany.

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-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 APPSwePSEN1dE9 mice. By contrast, homogenates from brains of APPSwePSEN1dE9 mice failed to induce seeding and spreading of amyloid-β pathology in ASC-deficient APPSwePSEN1dE9 mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid-β pathology in APPSwePSEN1dE9 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.

PMID:
29293211
DOI:
10.1038/nature25158
[Indexed for MEDLINE]

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