{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T01:53:59Z","timestamp":1791942839073,"version":"4.3.4"},"reference-count":64,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T00:00:00Z","timestamp":1673827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006021","name":"Direction G\u00e9n\u00e9rale de l\u2019Armement","doi-asserted-by":"publisher","award":["2020007"],"award-info":[{"award-number":["2020007"]}],"id":[{"id":"10.13039\/501100006021","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A broad range of data identify Ca2+-permeable amyloid pores as the most neurotoxic species of Alzheimer\u2019s \u03b2-amyloid peptide (A\u03b21\u201342). Following the failures of clinical trials targeting amyloid plaques by immunotherapy, a consensus is gradually emerging to change the paradigm, the strategy, and the target to cure Alzheimer\u2019s disease. In this context, the therapeutic peptide AmyP53 was designed to prevent amyloid pore formation driven by lipid raft microdomains of the plasma membrane. Here, we show that AmyP53 outcompetes A\u03b21\u201342 binding to lipid rafts through a unique mode of interaction with gangliosides. Using a combination of cellular, physicochemical, and in silico approaches, we unraveled the mechanism of action of AmyP53 at the atomic, molecular, and cellular levels. Molecular dynamics simulations (MDS) indicated that AmyP53 rapidly adapts its conformation to gangliosides for an optimal interaction at the periphery of a lipid raft, where amyloid pore formation occurs. Hence, we define it as an adaptive peptide. Our results describe for the first time the kinetics of AmyP53 interaction with lipid raft gangliosides at the atomic level. Physicochemical studies and in silico simulations indicated that A\u03b21\u201342 cannot interact with lipid rafts in presence of AmyP53. These data demonstrated that AmyP53 prevents amyloid pore formation and cellular Ca2+ entry by competitive inhibition of A\u03b21\u201342 binding to lipid raft gangliosides. The molecular details of AmyP53 action revealed an unprecedent mechanism of interaction with lipid rafts, offering innovative therapeutic opportunities for lipid raft and ganglioside-associated diseases, including Alzheimer\u2019s, Parkinson\u2019s, and related proteinopathies.<\/jats:p>","DOI":"10.3390\/ijms24021760","type":"journal-article","created":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T03:40:34Z","timestamp":1673840434000},"page":"1760","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["AmyP53 Prevents the Formation of Neurotoxic \u03b2-Amyloid Oligomers through an Unprecedent Mechanism of Interaction with Gangliosides: Insights for Alzheimer\u2019s Disease Therapy"],"prefix":"10.3390","volume":"24","author":[{"given":"Fodil","family":"Azzaz","sequence":"first","affiliation":[{"name":"INSERM UMR_S 1072, Aix Marseille University, 13015 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henri","family":"Chahinian","sequence":"additional","affiliation":[{"name":"INSERM UMR_S 1072, Aix Marseille University, 13015 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nouara","family":"Yahi","sequence":"additional","affiliation":[{"name":"INSERM UMR_S 1072, Aix Marseille University, 13015 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8653-5521","authenticated-orcid":false,"given":"Jacques","family":"Fantini","sequence":"additional","affiliation":[{"name":"INSERM UMR_S 1072, Aix Marseille University, 13015 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0655-7056","authenticated-orcid":false,"given":"Coralie","family":"Di Scala","sequence":"additional","affiliation":[{"name":"Neuroscience Center\u2014HiLIFE, Helsinki Institute of Life Science, University of Helsinki, 00014 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101580","DOI":"10.1016\/j.eclinm.2022.101580","article-title":"Global and regional projections of the economic burden of Alzheimer\u2019s disease and related dementias from 2019 to 2050: A value of statistical life approach","volume":"51","author":"Nandi","year":"2022","journal-title":"EClinicalMedicine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1002\/alz.12362","article-title":"Population estimate of people with clinical Alzheimer\u2019s disease and mild cognitive impairment in the United States (2020\u20132060)","volume":"17","author":"Rajan","year":"2021","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e12295","DOI":"10.1002\/trc2.12295","article-title":"Alzheimer\u2019s disease drug development pipeline: 2022","volume":"8","author":"Cummings","year":"2022","journal-title":"Alzheimer\u2019s Dement. 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