title: A synthetic amino acid substitution of Tyr10 in Aβ peptide sequence yields a dominant negative variant in amyloidogenesis.
abstract: Alzheimer's disease (AD) is the most common cause of dementia in elderly people, and age is the major nongenetic risk factor for sporadic AD. A hallmark of AD is the accumulation of amyloid in the brain, which is composed mainly of the amyloid beta-peptide (Aβ) in the form of oligomers and fibrils. However, how aging induces Aβ aggregation is not yet fully determined. Some residues in the Aβ sequence seem to promote Aβ-induced toxicity in association with age-dependent risk factors for AD, such as (i) increased GM1 brain membrane content, (ii) altered lipid domain in brain membrane, (iii) oxidative stress. However, the role of Aβ sequence in promoting aggregation following interaction with the plasma membrane is not yet demonstrated. As Tyr10 is implicated in the induction of oxidative stress and stabilization of Aβ aggregation, we substituted Tyr 10 with a synthetic amino acid that abolishes Aβ-induced oxidative stress and shows an accelerated interaction with GM1. This variant peptide shows impaired aggregation properties and increased affinity for GM1. It has a dominant negative effect on amyloidogenesis in vitro, in cellulo, and in isolated synaptosomes. The present study shed new light in the understanding of Aβ-membrane interactions in Aβ-induced neurotoxicity. It demonstrates the relevance of Aβ sequence in (i) Aβ-membrane interaction, underlining the role of age-dependent enhanced GM1 content in promoting Aβ aggregation, (ii) Aβ aggregation, and (iii) Aβ-induced oxidative stress. Our results open the way for the design of peptides aimed to inhibit Aβ aggregation and neurotoxicity.
authors.affiliation: IPBS, CNRS UMR 5089, Universite' de Toulouse, Toulouse, France.
authors.forename: Honoree
authors.initials: H
authors.lastname: Mazargui
authors.forename: Christian
authors.initials: C
authors.lastname: Lévêque
authors.forename: Dirk
authors.initials: D
authors.lastname: Bartnik
authors.forename: Jacques
authors.initials: J
authors.lastname: Fantini
authors.forename: Tiphany
authors.initials: T
authors.lastname: Gouget
authors.forename: Mariarosa A B
authors.initials: MA
authors.lastname: Melone
authors.forename: Susanne A
authors.initials: SA
authors.lastname: Funke
authors.forename: Dieter
authors.initials: D
authors.lastname: Willbold
authors.forename: Lorena
authors.initials: L
authors.lastname: Perrone
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D018384:Oxidative Stress / Q000502:physiology; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D014443:Tyrosine