RESUMEN
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 (Aß) in the form of oligomers and fibrils. However, how aging induces Aß aggregation is not yet fully determined. Some residues in the Aß sequence seem to promote Aß-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 Aß 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 Aß aggregation, we substituted Tyr 10 with a synthetic amino acid that abolishes Aß-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 Aß-membrane interactions in Aß-induced neurotoxicity. It demonstrates the relevance of Aß sequence in (i) Aß-membrane interaction, underlining the role of age-dependent enhanced GM1 content in promoting Aß aggregation, (ii) Aß aggregation, and (iii) Aß-induced oxidative stress. Our results open the way for the design of peptides aimed to inhibit Aß aggregation and neurotoxicity.
