β-Amyloid Clustering around ASC Fibrils Boosts Its Toxicity in Microglia
Open accessAbstract
Alzheimer's disease is the world's most common neurodegenerative disorder. It is associated with neuroinflammation involving activation of microglia by β-amyloid (Aβ) deposits. Based on previous studies showing apoptosis-associated speck-like protein containing a CARD (ASC) binding and cross-seeding extracellular Aβ, we investigate the propagation of ASC between primary microglia and the effects of ASC-Aβ composites on microglial inflammasomes and function. Indeed, ASC released by a pyroptotic cell can be functionally built into the neighboring microglia NOD-like receptor protein (NLRP3) inflammasome. Compared with protein-only application, exposure to ASC-Aβ composites amplifies the proinflammatory response, resulting in pyroptotic cell death, setting free functional ASC and inducing a feedforward stimulating vicious cycle. Clustering around ASC fibrils also compromises clearance of Aβ by microglia. Together, these data enable a closer look at the turning point from acute to chronic Aβ-related neuroinflammation through formation of ASC-Aβ composites.
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ASC specks can be recognized by neighboring microglia as a danger signal and induce inflammatory responses including activation of the NLRP3 inflammasome, thereby propagating inflammation.
“They can also be recognized by neighboring microglia as a danger signal and induce inflammatory responses including activation of the NLRP3 inflammasome, thereby propagating inflammation [70–72].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [72]
ASC-binding to Aβ induces pyroptosis and impairs microglial uptake and degradation of Aβ in primary mouse microglia.
“ASC-binding to Aβ induced pyroptosis and impaired microglial uptake and degradation of Aβ in primary mouse microglia, contributing to further pathology driven by these aggregates [72].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [72]
ASC-binding to Aβ contributes to further pathology driven by these aggregates.
“ASC-binding to Aβ induced pyroptosis and impaired microglial uptake and degradation of Aβ in primary mouse microglia, contributing to further pathology driven by these aggregates [72].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [72]
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“NLRP3 is a key component in the initiation of the inflammatory response, and the extracellular adaptor protein ASC has the ability to recruit and activate pro-casepase-1 and IL-18 contributing to neuronal death [59].”
BackgroundModulation of β-Amyloid Fibril Formation in Alzheimer’s Disease by Microglia and Infection
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- Authors
- Friker, L. L., Scheiblich, H., Hochheiser, I. V., Brinkschulte, R., Riedel, D., Latz, E., Geyer, M., & Heneka, M. T.
- Affiliations
- University of Bonn (DE)
- Max Planck Institute for Biophysical Chemistry (DE)
- Corresponding author
- Heneka, Michael T.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2020-03
- Volume
- 30
- Issue
- 11
- Pages
- 3743-3754.e6
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC8729885
- OpenAlex
- W3011845531
- Cited by
- 191
- References
- 15
- Citations by year
- 2026: 27 · 2025: 27 · 2024: 29 · 2023: 37 · 2022: 37 · 2021: 21 · 2020: 13
- FWCI
- 8.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DZNE Pub (submittedVersion, cc-by)
- Funders
- Roche
- Biogen
- Novartis Pharma
- Deutsche Forschungsgemeinschaft (EXC2151 – 390873048)
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- National Institutes of Health (R01 AG059752-02)
- Helmholtz Association
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- amyloid-beta, ASC, apoptosis-associated speck-like protein, microglia, NLRP3 inflammasome, pyroptosis, neuroinflammation, Alzheimer's disease, amyloid fibrils, amyloid clearance, pro-inflammatory response
- MeSH terms
- Pyroptosis, NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Cells, Cultured, Humans, Mice, Inbred C57BL, Models, Biological, Signal Transduction, Amyloid beta-Peptides, Microglia, Caspase 1, Toll-Like Receptor 2, Toll-Like Receptor 4, CARD Signaling Adaptor Proteins, Interleukin-1beta, Inflammasomes, Proteolysis
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