A synthetic amino acid substitution of Tyr10 in Aβ peptide sequence yields a dominant negative variant in amyloidogenesis

Aging Cell

Honoree Mazargui²  Christian Lévêque⁶  Dirk Bartnik¹  Jacques Fantini⁴  Tiphany Gouget³  Mariarosa A. B. Melone⁵  Susanne A. Funke¹  Dieter Willbold¹ 

[1] Institute of Complex Systems (ICS-6), Forschungszentrum Jülich, Jülich, Germany;IPBS, CNRS UMR 5089, Universite’ de Toulouse, Toulouse, France;NICN, CNRS UMR 6184, Faculté de Médecine, Université Aix-Marseille, Marseille, France;Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CNRS UMR 6231, Université Paul Cézanne (Aix-Marseille 3), Université de la Méditerranée (Aix-Marseille 2), Marseille, France;Division of Clinical Neurology, Department of Clinical and Experimental Medicine and Surgery “F. Magrassi e A. Lanzara” Second University of Naples, Naples, Italy;Aix-Marseille Univ, UMR 1072, 13015, Marseille, France and INSERM, UMR 1072, 13015, Marseille, France

关键词: aggregation;    Alzheimer;    amyloid;    GM1;    oxidative stress;    rafts;   

DOI  :  10.1111/j.1474-9726.2012.00814.x

来源: Wiley

【 摘 要 】

Summary

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.

【 授权许可】

Unknown   
© 2012 The Authors. Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland