title: The effects of AbetaPP mutations and APOE polymorphisms on cerebral amyloid angiopathy.
abstract: Analysis of causative mutations and genetic risk factors aid in the understanding of important processes of cerebral amyloid angiopathy (CAA) in humans. We identified a mutation at a novel site of the beta-amyloid precursor protein (AbetaPP) gene associated with familial CAA; this mutation causes an aspartate to asparagine substitution at position 23 of the Abeta peptide. Neuropathological analysis of a 68-year-old man with this mutation showed dramatic Abeta deposition in blood vessels, diffiuse parenchymal Abeta deposits, dystrophic neurites and neurofibrillary tangles. The Abeta deposition showed complete co-localization of Abeta40 and Abeta42, compared to the predominant Abeta42 deposition seen in AD. We hypothesize that the loss of an acidic residue at position 23 of Abeta might be important in the process of Abeta aggregation on smooth muscle cells on the cerebrovasculature. We also analyzed how the apolipoprotein E (APOE) gene might influence aggregation of Abeta by examining the physical association of apoE domains with Abeta via immunohistochemistry. We found that the lipid-binding domain of apoE was more strongly associated with Abeta than the receptor-binding domain, and that 40% of all Abeta deposits had no apoE bound to them. We suggest that the initial deposition of Abeta occurs in the absence of apoE, and that the process of Abeta deposit growth or stabilization is apoE-dependent.
authors.affiliation: Alzheimer Research Unit, Massachusetts General Hospital, Charlestown 02129, USA. rebeck@helix.mgh.harvard.edu
authors.forename: G W
authors.initials: GW
authors.lastname: Rebeck
authors.forename: H S
authors.initials: HS
authors.lastname: Cho
authors.forename: T J
authors.initials: TJ
authors.lastname: Grabowski
authors.forename: S M
authors.initials: SM
authors.lastname: Greenberg
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D028243:Cerebral Amyloid Angiopathy, Familial / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense
chemical_list: D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E