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beta-Amyloid activates complement by binding to a specific region of the collagen-like domain of the C1q A chain.
Abstract
beta-amyloid peptides that accumulate within the brain of individuals with Alzheimer's disease bind to C1q and activate the classical C pathway via a specific interaction with a site within the collagen-like domain of C1q (C1q-CLF). Synthetic analogues of beta-amyloid peptides, beta 1-42 and beta 1-40, bound to C1q and were strong activators of C as assessed by both total C consumption and C4 consumption. beta 1-42 was significantly more effective than beta 1-40 in binding to C1q and triggering C activation, whereas beta 1-28 demonstrated little or no binding or C activation. This C-activating capacity seems to be largely correlated with the assembly of the beta 1-42 into low speed sedimentable aggregates and/or macromolecular fibrils. Radiolabeled C1q and C1q-CLF bind specifically to these aggregates or amyloid fibrils. In addition, using synthetic C1q peptides in a solid phase binding assay, the major binding site of beta 1-42 to C1q was localized to the C1q A chain collagen-like residues 14-26, a region previously described as a novel interaction site for Ab-independent activators of C1. C1q A chain peptide 14-26 blocked the ability of beta-amyloid peptides to activate the classical C pathway, providing evidence that this relatively unrecognized mechanism of C activation (via binding to the C1q-CLF) may have crucial physiologic consequences. Finally, these observations provide further support for the hypothesis that C activation and inflammation may be a component in the pathogenesis of AD and suggest possibilities for modulating the progression of AD.
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“However, several complement subunits also play key roles in microglia-mediated synapse destruction during AD progression74–76”
From Trisomy 21 causes changes in the circulating proteome indicative of chronic autoinflammation (2017) · cites this paper as [74]
In the citing paper
“Upregulation of C1q, which is known to bind to Aβ peptides [69], NFT filaments [70], apoptotic cells and extracellular debris [71], indicated that the classical activation pathway was activated.”
In the citing paper
“it is noteworthy that C1q binding to Aβ can trigger activation of the classical complement cascade (Jiang et al., 1994; Rosen and Stevens, 2010).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Jiang et al., 1994
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Koch, B. M. E. (2019) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-7716
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Metadata
- Authors
- Jiang, H., Burdick, D., Glabe, C. G., Cotman, C. W., & Tenner, A. J.
- Affiliations
- University of California, Irvine (US)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 1994-05
- Volume
- 152
- Issue
- 10
- Pages
- 5050-5059
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1549447146
- Cited by
- 330
- References
- 0
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 9 · 2023: 9 · 2022: 6 · 2021: 4 · 2020: 13 · 2019: 11 · 2018: 4 · 2017: 8 · 2016: 6 · 2015: 4 · 2014: 8 · 2013: 5 · 2012: 9
- FWCI
- 10.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (5T32 CA 09054, T32CA009054)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid-beta, C1q, classical complement pathway, complement activation, collagen-like domain, amyloid fibrils, Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Amino Acid Sequence, Binding Sites, Collagen, Complement Activation, Humans, Molecular Sequence Data, Complement C1q, Amyloid beta-Peptides
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