title: Pathogenic effects of cerebral amyloid angiopathy mutations in the amyloid beta-protein precursor.
abstract: Cerebral amyloid beta-protein angiopathy (CAA) is a key pathological feature of patients with Alzheimer's disease and certain related disorders. Several mutations have been identified within the Abeta region of the Abeta protein precursor (AbetaPP) gene that appear to enhance the severity of CAA. A new mutation has been identified within the Abeta region (D23N) of AbetaPP that is associated with severe CAA in an Iowa kindred. Recently, we showed that E22Q Dutch, D23N Iowa, and E22Q/D23N Dutch/Iowa double-mutant Abeta40 peptides rapidly assemble in solution to form fibrils compared to wild-type Abeta40. Similarly, the E22Q Dutch and D23N Iowa Abeta40 peptides were found to induce robust pathologic responses in cultured human cerebrovascular smooth muscle (HCSM) cells, including elevated levels of cell-associated AbetaPP, proteolytic breakdown of actin, and cell death. Double-mutant E22Q/D23N Dutch/Iowa Abeta40 was more potent than either single-mutant form of Abeta in causing pathologic responses in HCSM cells. These in vitro data suggested that the E22Q Dutch and D23N Iowa substitutions promote fibrillogenesis and the pathogenicity of Abeta towards HCSM cells. Moreover, the presence of both CAA substitutions in the same Abeta peptide further enhances the fibrillogenic and pathogenic properties of Abeta. We also have generated transgenic mouse models to examine the effects of single and double CAA mutations in AbetaPP in vivo. Preliminary analysis of transgenic mouse brains indicates that expression of double-mutant E22Q/D23N Dutch/Iowa AbetaPP leads to robust deposition of Abeta in a vascular-weighted manner.
authors.affiliation: Departments of Medicine and Pathology, HSC T-15/081, Health Sciences Center, State University of New York, Stony Brook, NY 11794-8153, USA. William.VanNostrand@stonybrook.edu
authors.forename: William E
authors.initials: WE
authors.lastname: Van Nostrand
authors.forename: Jerry P
authors.initials: JP
authors.lastname: Melchor
authors.forename: Galina
authors.initials: G
authors.lastname: Romanov
authors.forename: Kelly
authors.initials: K
authors.lastname: Zeigler
authors.forename: Judianne
authors.initials: J
authors.lastname: Davis
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D001530:Belgium; D028243:Cerebral Amyloid Angiopathy, Familial / Q000145:classification / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007484:Iowa; D008969:Molecular Sequence Data; D009154:Mutation; D009426:Netherlands
chemical_list: D016564:Amyloid beta-Protein Precursor