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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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“A long-established finding showed that the assembly of Ab aggregates was critical for binding of C1q and activation of complement (Jiang et al. 1994).”
BackgroundInflammation, Apoptosis, and Alzheimer's Disease
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Modular Organization of the Carboxyl-Terminal, Globular Head Region of Human C1q A, B, and C Chains
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“Recently, it has been shown that C1q interaction with fibrils of the A 1-42 is likely to take place through the gC1q region (44), contrary to an earlier report suggesting an involvement of residues 14-26 within the C1q A chain CLR in C1q-A 1-42 interaction (45).”
ResultAstrocytes from old Alzheimer's disease mice are impaired in Aβ uptake and in neuroprotection
Iram, T., Trudler, D., Kain, D., Kanner, S., Galron, R., Vassar, R. J., Barzilai, A., Blinder, P., Fishelson, Z., & Frenkel, D. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.08.001 · Cited by 121
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“In vitro studies have shown that fibrillar Aβ (fAß) can activate the classical complement pathway (in the absence of antibody) and the alternative pathway [76, 77].”
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“Fibrillar Aß can activate the classical complement pathway (in the absence of antibody) or the alternative complement pathway in vitro [19, 20] and in vivo as evidenced by the association of complement components with fAß plaques in human AD and mouse models of AD [2, 21, 22].”
BackgroundSelf-citationThe effect of insomnia on development of Alzheimer’s disease
Sadeghmousavi, S., Eskian, M., Rahmani, F., & Rezaei, N. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01960-9 · Cited by 121
“For example, Aβ accumulations can directly activate the complement proteins [168], then the complement proteins can accelerate the aggregation of Aβ so it is a bidirectional relationship [169, 170] and as more Aβ becomes aggregated better, it can activate complement component (Clq) [171].”
BackgroundThe role of complement in Alzheimer’s disease pathology
Emmerling, M. R., Watson, M. D., Raby, C. A., & Spiegel, K. (2000) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/s0925-4439(00)00042-9 · Cited by 110
The C1q Family of Proteins: Insights into the Emerging Non-Traditional Functions
Ghebrehiwet, B., Hosszu, K., Valentino, A., & Peerschke, E. I. B. (2012) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00052 · Cited by 106
“…such as gp41 (Ebenbichler et al., 1991), acute phase proteins such as C-reactive protein (Jiang et al., 1991; Gewurz et al., 1993), bacterial and mitochondrial membranes (Gewurz et al., 1993), DNA (Jiang et al., 1991), as well as β-amyloid peptide (Jiang et al., 1994; Tacnet-Delorme et al., 2001).”
BackgroundC1q and phagocytosis: the perfect complement to a good meal
Galvan, M. D., Greenlee‐Wacker, M. C., & Bohlson, S. S. (2012) · Journal of Leukocyte Biology · doi:10.1189/jlb.0212099 · Cited by 113
Webster, S. D., Galvan, M. D., Ferran, E., Garzon-Rodriguez, W., Glabe, C. G., & Tenner, A. J. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.12.7496 · Cited by 104
“can result in acceleration of A b aggregation in the absence of C1r, C1s, and other complement proteins (39) and can lead to activation of complement when C1q is complexed with the serine proteases C1r and C1s (as the macromolecule, C1) in the presence of a functional complement system (40, 41).”
BackgroundSelf-citationThe unsolved relationship of brain aging and late-onset Alzheimer disease
Kern, A., & Behl, C. (2009) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2009.07.016 · Cited by 108
“Mechanisms that have been approved to the toxicity of Aβ include activation of inflammation [138,139], damage to mitochondria [140,141] and”
BackgroundBoche, D., & Nicoll, J. A. R. (2008) · Brain Pathology · doi:10.1111/j.1750-3639.2008.00134.x · Cited by 106
“Fibrillar Ab is a strong stimulator of the complement system (94) and can activate the classical (antibody-dependent) (2, 20, 57, 69, 117) and alternative (antibody-independent) (13, 111) pathways.”
BackgroundPisalyaput, K., & Tenner, A. J. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.05012.x · Cited by 103
“In vitro fibrillar amyloid peptide can directly activate complement and complement proteins have been found associated with fibrillar Ab deposits in human AD (Eikelenboom et al. 1989; Rogers et al. 1992; Jiang et al. 1994).”
BackgroundSelf-citationHead, E., Azizeh, B. Y., Lott, I. T., Tenner, A. J., Cotman, C. W., & Cribbs, D. H. (2001) · Neurobiology of Disease · doi:10.1006/nbdi.2000.0380 · Cited by 103
“Fibrillar forms of Ab can bind and activate C1, the first component of the classical C9 pathway (Jiang et al., 1994; Rogers et al., 1992; Webster et al., 1997).”
BackgroundSelf-citationKeene, C. D., Cudaback, E., Li, X., Montine, K. S., & Montine, T. J. (2011) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2011.08.002 · Cited by 103
β-Amyloid Converts an Acute Phase Injury Response to Chronic Injury Responses
Cotman, C. W., Tenner, A. J., & Cummings, B. J. (1996) · Neurobiology of Aging · doi:10.1016/0197-4580(96)00117-0 · Cited by 101
Self-citationThe Proteomics of DrusenPreprint
Crabb, J. W. (2014) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a017194 · Cited by 106
“Ab has also been reported to activate complement (Rogers et al. 1992; Jiang et al. 1994) and other pattern recognition receptors, including RAGE (Chen et al. 2007; Schmidt et al. 2009) and toll-like receptors (Fassbender et al. 2004; Liu et al. 2005).”
BackgroundComplement-Mediated Events in Alzheimer’s Disease: Mechanisms and Potential Therapeutic Targets
Tenner, A. J. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.1901068 · Cited by 102
“In AD, the complement system may be continually activated by both fibrillar Ab (88, 115) and extracellular tangles formed by hyperphosphorylated t (87).”
BackgroundSelf-citationEikelenboom, P., Rozemüller, A. J. M., & Muiswinkel, F. L. V. (1998) · Experimental Neurology · doi:10.1006/exnr.1998.6920 · Cited by 98
Inflammation in transgenic mouse models of neurodegenerative disorders
Schwab, C., Klegeris, A., & McGeer, P. L. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.10.013 · Cited by 97
“Matsuoka and colleagues [23] showed that mouse C1q strongly colocalized with fibrillary Aβ, and was also upregulated in some plaque-associatedmicroglia in PS/APPmice.”
BackgroundInfluentialThe complement cascade in Alzheimer’s disease: a systematic review and meta-analysis
Krance, S. H., Wu, C., Zou, Y. Z., Mao, H., Toufighi, S., He, X., Pakosh, M. T., & Swardfager, W. (2019) · Molecular Psychiatry · doi:10.1038/s41380-019-0536-8 · Cited by 97
Bohlson, S. S., & Tenner, A. J. (2023) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101921-035639 · Cited by 105
Self-citationPasinetti, G. M. (2001) · Archives of Gerontology and Geriatrics · doi:10.1016/s0167-4943(01)00091-7 · Cited by 91
The Inflammatory Response in Alzheimer's Disease
Rogers, J. (2008) · Journal of Periodontology · doi:10.1902/jop.2008.080171 · Cited by 92
AßT Amyloidogenesis: Unique, or Variation on a Systemic Theme
Kisilevsky, R., Fraser, P. E., & Benson, M. D. (1997) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409239709082674 · Cited by 92
Wick, G., & Grubeck‐Loebenstein, B. (1997) · Immunological Reviews · doi:10.1111/j.1600-065x.1997.tb01037.x · Cited by 92
Yin and Yang: complement activation and regulation in Alzheimer’s disease
Shen, Y., & Meri, S. (2003) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2003.08.001 · Cited by 91
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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