title: The Tottori (D7N) and English (H6R) familial Alzheimer disease mutations accelerate Abeta fibril formation without increasing protofibril formation.
abstract: A subset of Alzheimer disease cases is caused by autosomal dominant mutations in genes encoding the amyloid beta-protein precursor or presenilins. Whereas some amyloid beta-protein precursor mutations alter its metabolism through effects on Abeta production, the pathogenic effects of those that alter amino acid residues within the Abeta sequence are not fully understood. Here we examined the biophysical effects of two recently described intra-Abeta mutations linked to early-onset familial Alzheimer disease, the D7N Tottori-Japanese and H6R English mutations. Although these mutations do not affect Abeta production, synthetic Abeta(1-42) peptides carrying D7N or H6R substitutions show enhanced fibril formation. In vitro analysis using Abeta(1-40)-based mutant peptides reveal that D7N or H6R mutations do not accelerate the nucleation phase but selectively promote the elongation phase of amyloid fibril formation. Notably, the levels of protofibrils generated from D7N or H6R Abeta were markedly inhibited despite enhanced fibril formation. These N-terminal Abeta mutations may accelerate amyloid fibril formation by a unique mechanism causing structural changes of Abeta peptides, specifically promoting the elongation process of amyloid fibrils without increasing metastable intermediates.
authors.affiliation: Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hori
authors.affiliation: Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Neurology and Tottori University, Tottori, 683-8504, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Wakutani
authors.affiliation: Biological Regulation, Tottori University, Tottori, 683-8504, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Urakami
authors.affiliation: Neurology and Tottori University, Tottori, 683-8504, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakashima
authors.affiliation: Department of Neurology, David Geffen School of Medicine, and Brain Research Institute and Molecular Biology Institute, University of California, Los Angeles, California 90095, and the.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Condron
authors.affiliation: RIKEN Brain Science Institute, Wako, 351-0198, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tsubuki
authors.affiliation: RIKEN Brain Science Institute, Wako, 351-0198, Japan.
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
authors.affiliation: Department of Neurology, David Geffen School of Medicine, and Brain Research Institute and Molecular Biology Institute, University of California, Los Angeles, California 90095, and the.
authors.forename: David B
authors.initials: DB
authors.lastname: Teplow
authors.affiliation: Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. Electronic address: iwatsubo@mol.f.u-tokyo.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D020125:Mutation, Missense; D010455:Peptides / Q000737:chemistry* / Q000235:genetics; D053763:Presenilins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D010455:Peptides; D053763:Presenilins