The Tottori (D7N) and English (H6R) familial Alzheimer disease mutations accelerate Abeta fibril formation without increasing protofibril formation.
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.
Hori
Yukiko
Y
Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Hashimoto
Tadafumi
T
Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Wakutani
Yosuke
Y
Neurology and Tottori University, Tottori, 683-8504, Japan.
Urakami
Katsuya
K
Biological Regulation, Tottori University, Tottori, 683-8504, Japan.
Nakashima
Kenji
K
Neurology and Tottori University, Tottori, 683-8504, Japan.
Condron
Margaret M
MM
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.
Tsubuki
Satoshi
S
RIKEN Brain Science Institute, Wako, 351-0198, Japan.
Saido
Takaomi C
TC
RIKEN Brain Science Institute, Wako, 351-0198, Japan.
Teplow
David B
DB
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.
Iwatsubo
Takeshi
T
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.
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
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D010455:Peptides; D053763:Presenilins