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

Carmen Venegas; Sathish Kumar; Bernardo S Franklin; Tobias Dierkes; Rebecca Brinkschulte; Dario Tejera; Ana Vieira-Saecker; Stephanie Schwartz; Francesco Santarelli; Markus P Kummer; Angelika Griep; Ellen Gelpi; Michael Beilharz; Dietmar Riedel; Douglas T Golenbock; Matthias Geyer; Jochen Walter; Eicke Latz; Michael T Heneka

doi:10.1038/nature25158

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

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

Authors

Carmen Venegas¹, Sathish Kumar², Bernardo S Franklin³, Tobias Dierkes^{1

3}, Rebecca Brinkschulte³, Dario Tejera¹, Ana Vieira-Saecker¹, Stephanie Schwartz¹, Francesco Santarelli¹, Markus P Kummer¹, Angelika Griep¹, Ellen Gelpi⁴, Michael Beilharz³, Dietmar Riedel⁵, Douglas T Golenbock⁶, Matthias Geyer³, Jochen Walter², Eicke Latz^{3

6

7}, Michael T Heneka^{1

6

7}

Affiliations

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.

PMID: 29293211
DOI: 10.1038/nature25158

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 APP_SwePSEN1_dE9 mice. By contrast, homogenates from brains of APP_SwePSEN1_dE9 mice failed to induce seeding and spreading of amyloid-β pathology in ASC-deficient APP_SwePSEN1_dE9 mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid-β pathology in APP_SwePSEN1_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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / metabolism*
Alzheimer Disease / pathology
Amyloid beta-Peptides / metabolism*
Amyloid beta-Protein Precursor / deficiency
Amyloid beta-Protein Precursor / genetics
Animals
Antibodies / administration & dosage
Antibodies / immunology
Antibodies / pharmacology
CARD Signaling Adaptor Proteins / antagonists & inhibitors
CARD Signaling Adaptor Proteins / chemistry
CARD Signaling Adaptor Proteins / immunology
CARD Signaling Adaptor Proteins / metabolism*
Female
Hippocampus / cytology
Hippocampus / metabolism
Hippocampus / pathology
Humans
Inflammasomes / immunology
Inflammasomes / metabolism
Inflammation / metabolism
Inflammation / pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Microglia / metabolism*
Presenilin-1 / deficiency
Presenilin-1 / genetics
Protein Aggregation, Pathological*
Protein Domains
Spatial Memory / physiology

Substances

Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Antibodies
CARD Signaling Adaptor Proteins
Inflammasomes
PYCARD protein, human
Presenilin-1
Pycard protein, mouse
presenilin 1, mouse