Aspartate residue 7 in amyloid β-protein is critical for classical complement pathway activation: Implications for Alzheimer's disease pathogenesis (original) (raw)
- Article
- Published: 01 January 1997
Nature Medicine volume 3, pages 077–079 (1997)Cite this article
- 325 Accesses
- 137 Citations
- Metrics details
Abstract
Fibrillar amyloid β-protein has been implicated in the pathogenesis of Alzheimer's disease because of its neurotoxicity and its ability to activate complement1–3. Reactive microglia, astrocytes4,5 and complement (C') components (reviewed in ref. 6) are associated with senile plaques, the fibrillar, β-sheet assemblies of amyloid β-peptide found predominantly in brain from individuals with AD (ref. 7). These indications of inflammatory events are not prevalent in the nonfibrillar “diffuse” plaques often seen in age-matched control cases without dementia. Clinical studies over the past several years have correlated the use of anti-inflammatory drugs with a decrease in the incidence and progression of AD dementia and/or dysfunction, supporting a role for gliosis and inflammation in AD pathogenesis8,9 (reviewed in ref. 6). C5a, a product of C' activation, is chemotactic for microglia10. Thus, complement activation provides a specific mechanism for recruiting reactive glial cells to the site of the fibrillar amyloid β-protein plaque, which could lead to inflammatory events, neuronal dysfunction and degeneration5. With the use of truncated amyloid β-peptides, the region of amyloid β-protein limited by residues 4 and 11 has been identified as critical in the interaction between amyloid β-protein and C1q, the recognition component of the classical complement pathway (CCP), which results in the activation of C'. Furthermore, substitution of an isoaspartic acid for aspartic acid at amyloid β-protein residue 7 resulted in the complete elimination of CCP-activating activity. A molecular model of this interaction has been generated that should be useful in the design of candidate therapeutic inhibitors of CCP activation by amyloid β-protein.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Additional access options:
Similar content being viewed by others
References
- Hsiao, K.K. et al. Correlative memory deficits, Ap elevations, and amyloid plaques in transgenic mice. Science 274, 99–102 (1996).
Article CAS PubMed Google Scholar - Selkoe, D.J. The molecular pathology of Alzheimer's disease. Neuron 6, 487–498 (1991).
Article CAS PubMed Google Scholar - Jiang, H., Burdick, D., Glabe, C.G., Cotman, C.W. & Tenner, A.J. β-Amyloid activates complement by binding to a specific region of the collagen-like domain of the C1q A chain. J.Immunol. 152, 5050–5059 (1994).
CAS PubMed Google Scholar - Maat-Schieman, M.L.C. et al. Microglia in diffuse plaques in hereditary cerebral hemorrhage with amyloidosis (Dutch): An immunohistochemical study. J. Neuropathol. Exp. Neurol. 5, 483–491 (1994).
Article Google Scholar - Cotman, C.W., Tenner, A.J. & Cummings, B.J. β-Amyloid converts an acute phase injury response to chronic injury responses. Neurobiol. Aging 17, 723–731 (1996).
Article CAS PubMed Google Scholar - Pasinetti, G.M. Inflammatory mechanisms in neurodegeneration and Alzheimer's disease: The role of the complement system. Neurobiol. Aging 17, 707–716 (1996).
Article CAS PubMed Google Scholar - Afagh, A., Cummings, B.J., Cribbs, D.H., Cotman, C.W. & Tenner, A.J. Localization and cell association of C1q in Alzheimer's disease brain. Exp. Neurol. 138, 22–32 (1996).
Article CAS PubMed Google Scholar - Breitner, J.C.S. et al. Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Neurobiol. Aging 4, 523–530 (1995).
Article Google Scholar - McGeer, P.L., McGeer, E., Rogers, J. & Sibley, J. Anti-inflammatory drugs and Alzheimer disease. Lancet 335, 1037 (1990).
Article CAS Google Scholar - Yao, J., Harvath, L., Gilbert, D.L. & Colton, C.A. Chemotaxis by a CNS macrophage, the microglia. J. Neurosci. Res. 27, 36–42 (1990).
Article CAS PubMed Google Scholar - Pike, C.J., Overman, M.J. & Cotman, C.W. Amino-terminal deletions enhance aggregation of β-amyloid peptides in vitro. J. Biol. Chem. 270, 23895–23898 (1995).
Article CAS PubMed Google Scholar - Hilbich, C., Kisters-Woike, B., Reed, J., Masters, C.L. & Beyreuther, K. Human and rodent sequence analogs of Alzheimer's amyloid beta A4 share similar properties and can be solubilized in buffers of pH 7.4. Eur. J. Biochem. 201, 61–69 (1991).
Article CAS PubMed Google Scholar - Johnson, B.A. et al. Protein L-isoaspartyl methyltransferse in postmortem brains of aged humans. Neurobiol. Aging 12, 19–24 (1991).
Article CAS PubMed Google Scholar - Roher, A.E. et al. Structural alterations in the peptide backbone of beta-amyloid core protein may account for its deposition and stability in Alzheimer's disease. J. Biol. Chem. 268, 3072–3083 (1993).
CAS PubMed Google Scholar - Bella, J., Eaton, M., Brodsky, B. & Berman, H.M. Crystal and molecular structure of a collagen-like peptide at 1.9 angstrom resolution. Science 266, 75–81 (1994).
Article CAS PubMed Google Scholar - Nomizu, M. et al. The all-D-configuration segment containing the IKVAV sequence of laminin A chain has similar activities to the all-L-peptide in vitro and in vivo. J. Biol. Chem. 267, 14118–14121 (1992).
CAS PubMed Google Scholar - Rogers, J. et al. Complement activation by beta-amyloid in Alzheimer disease. Proc. Natl. Acad. Sci. USA 89, 10016–10020 (1992).
Article CAS PubMed PubMed Central Google Scholar - Yao, J., Keri, J.E., Taffs, R.E. & Colton, C.A. Characterization of interleukin-1 production by microglia in culture. Brain Res. 591, 88–93 (1992).
Article CAS PubMed Google Scholar - Gasque, P., Fontaine, M. & Morgan, B.P. Complement expression in human brain: Biosynthesis of terminal pathway components and regulators in human glial cells and cell lines. J. Immunol. 154, 4726–4733 (1995).
CAS PubMed Google Scholar - Colton, C.A. & Gilbert, D.L. Microglia, an in vivo source of reactive oxygen species in the brain. Adv. Neurol. 59, 321–326 (1993).
CAS PubMed Google Scholar - Meda, L. et al. Activation of microglial cells by β-amyloid protein and interferon-gamma. Nature 374, 647–650 (1995).
Article CAS PubMed Google Scholar - El Khoury, J. et al. Scavenger receptor-mediated adhesion of microglia to β-amyloid fibrils. Nature 382, 716–719 (1996).
Article CAS PubMed Google Scholar - Paresce, D., Ghosh, R.N. & Maxfield, F.R. Microglial cells internalize aggregates of the Alzheimer's disease amyloid β-protein via a scavenger receptor. Neuron 17, 553–565 (1996).
Article CAS PubMed Google Scholar - Yan, S.D. et al. RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease. Nature 382, 685–691 (1996).
Article CAS PubMed Google Scholar - Kilchherr, E., Hofmann, H., Steigemann, W. & Engel, J. Structural model of the collagen-like region of C1q comprising the kink region and the fibre-like packing of the six triple helices. J. Mol. Biol. 186, 403–416 (1985).
Article CAS PubMed Google Scholar
Author information
Authors and Affiliations
- Department of Molecular Biology and Biochemistry, University of California, 3205 Biological Sciences II, Irvine, California, 92697, USA
Peter Velazquez, Thomas L. Poulos & Andrea J. Tenner - Department of Neurology and Institute for Brain Aging and Dementia, University of California, 1336 Biological Sciences II, Irvine, California, 92697, USA
David H. Cribbs
Authors
- Peter Velazquez
You can also search for this author inPubMed Google Scholar - David H. Cribbs
You can also search for this author inPubMed Google Scholar - Thomas L. Poulos
You can also search for this author inPubMed Google Scholar - Andrea J. Tenner
You can also search for this author inPubMed Google Scholar
Rights and permissions
About this article
Cite this article
Velazquez, P., Cribbs, D., Poulos, T. et al. Aspartate residue 7 in amyloid β-protein is critical for classical complement pathway activation: Implications for Alzheimer's disease pathogenesis.Nat Med 3, 077–079 (1997). https://doi.org/10.1038/nm0197-77
- Received: 17 September 1996
- Accepted: 25 November 1996
- Issue Date: 01 January 1997
- DOI: https://doi.org/10.1038/nm0197-77