title: Aspartate residue 7 in amyloid beta-protein is critical for classical complement pathway activation: implications for Alzheimer's disease pathogenesis.
abstract: Fibrillar amyloid beta-protein has been implicated in the pathogenesis of Alzheimer's disease because of its neurotoxicity and its ability to activate complement. Reactive microglia, astrocytes and complement (C') components (reviewed in ref. 6) are associated with senile plaques, the fibrillar, beta-sheet assemblies of amyloid beta-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 pathogenesis (reviewed in ref. 6). C5a, a product of C' activation, is chemotactic for microglia. Thus, complement activation provides a specific mechanism for recruiting reactive glial cells to the site of the fibrillar amyloid beta-protein plaque, which could lead to inflammatory events, neuronal dysfunction and degeneration. With the use of truncated amyloid beta-peptides, the region of amyloid beta-protein limited by residues 4 and 11 has been identified as critical in the interaction between amyloid beta-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 beta-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 beta-protein.
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine 92697, USA.
authors.forename: P
authors.initials: P
authors.lastname: Velazquez
authors.forename: D H
authors.initials: DH
authors.lastname: Cribbs
authors.forename: T L
authors.initials: TL
authors.lastname: Poulos
authors.forename: A J
authors.initials: AJ
authors.lastname: Tenner
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism*; D001665:Binding Sites; D003094:Collagen / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D051381:Rats; D017386:Sequence Homology, Amino Acid
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D001224:Aspartic Acid; D003094:Collagen