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Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer's disease
Carmen Venegas1, Sathish Kumar2, Bernardo S Franklin3
1Department of Neurodegenerative Diseases and Gerontopsychiatry, University of Bonn, Sigmund-Freud-Strasse 25, 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.
Insights
Inflammasome-activated ASC specks released by microglia act as a cross-seed, driving amyloid-beta pathology spread in Alzheimer's disease models. Blocking ASC specks reduces this pathology, highlighting inflammasome activation's role.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Neurodegenerative disorders feature pathology spread within and between brain areas.
- Alzheimer's disease involves amyloid-beta deposition, innate immune activation, and inflammasome-dependent ASC speck formation in microglia.
Purpose of the Study:
- To investigate the role of inflammasome-derived ASC specks in seeding and spreading amyloid-beta pathology.
- To determine if ASC specks act as a cross-seed for amyloid-beta pathology in Alzheimer's disease.
Main Methods:
- Intrahippocampal injection of ASC specks into APPSwePSEN1dE9 mice.
- Utilizing ASC-deficient APPSwePSEN1dE9 mice to assess pathology induction.
- Employing an anti-ASC antibody to block ASC speck effects.
Main Results:
- Intrahippocampal injection of ASC specks induced spreading of amyloid-beta pathology in APPSwePSEN1dE9 mice.
- Brain homogenates from APPSwePSEN1dE9 mice failed to induce pathology in ASC-deficient mice.
- Co-application of anti-ASC antibody inhibited the increase in amyloid-beta pathology.
Conclusions:
- Inflammasome activation and ASC speck formation are linked to the seeding and spreading of amyloid-beta pathology.
- ASC specks function as an inflammation-driven cross-seed for amyloid-beta pathology.
- These findings support inflammasome activation as a key factor in Alzheimer's disease progression.
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