title: The Osaka FAD mutation E22Δ leads to the formation of a previously unknown type of amyloid β fibrils and modulates Aβ neurotoxicity.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cerebral deposition of amyloid fibrils formed by the amyloid β (Aβ) peptide. Aβ has a length of 39-43 amino acid residues; the predominant Aβ isoforms are Aβ1-40 and Aβ1-42. While the majority of AD cases occur spontaneously, a subset of early-onset familial AD cases is caused by mutations in the genes encoding the Aβ precursor protein or presenilin 1/presenilin 2. Recently, a deletion of glutamic acid at position 22 within the Aβ sequence (E22Δ) was identified in Japanese patients with familial dementia, but the aggregation properties of the deletion variant of Aβ are not well understood. We investigated the aggregation characteristics and neurotoxicity of recombinantly expressed Aβ isoforms 1-40 and 1-42 with and without the E22Δ mutation. We show that the E22Δ mutation strongly accelerates the fibril formation of Aβ1-42 E22Δ compared to Aβ1-42 wild type (wt). In addition, we demonstrate that fibrils of Aβ1-40 E22Δ form a unique quaternary structure characterized by a strong tendency to form fibrillar bundles and a strongly increased thioflavin T binding capacity. Aβ1-40 E22Δ was neurotoxic in rat primary neuron cultures as compared to nontoxic Aβ1-40 wt. Aβ1-42 E22Δ was less toxic than Aβ1-42 wt, but it significantly decreased neurite outgrowth per cell in neuronal primary cultures. Because Aβ1-40 is the major Aβ form in vivo, the gain of toxic function caused by the E22 deletion may explain the development of familial AD in mutation carriers.
authors.affiliation: Institute of Molecular Biology and Biophysics, ETH Zurich, Schafmattstrasse 20, CH-8093 Zurich, Switzerland.
authors.forename: Oxana Yu
authors.initials: OY
authors.lastname: Ovchinnikova
authors.forename: Verena H
authors.initials: VH
authors.lastname: Finder
authors.forename: Ivana
authors.initials: I
authors.lastname: Vodopivec
authors.forename: Roger M
authors.initials: RM
authors.lastname: Nitsch
authors.forename: Rudi
authors.initials: R
authors.lastname: Glockshuber
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics*; D000818:Animals; D052160:Benzothiazoles; D002478:Cells, Cultured; D006801:Humans; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D009498:Neurotoxins / Q000737:chemistry / Q000235:genetics*; D051381:Rats; D013844:Thiazoles / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D009498:Neurotoxins; D013844:Thiazoles; C544092:beta-amyloid peptide 1-42 (E22delta) click peptide; C009462:thioflavin T