AmyP53 Prevents the Formation of Neurotoxic β-Amyloid Oligomers through an Unprecedent Mechanism of Interaction with Gangliosides: Insights for Alzheimer’s Disease Therapy - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue International Journal of Molecular Sciences Année : 2023

AmyP53 Prevents the Formation of Neurotoxic β-Amyloid Oligomers through an Unprecedent Mechanism of Interaction with Gangliosides: Insights for Alzheimer’s Disease Therapy

Résumé

A broad range of data identify Ca 2+-permeable amyloid pores as the most neurotoxic species of Alzheimer's β-amyloid peptide (Aβ 1-42). 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's 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 Aβ 1-42 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 Aβ 1-42 cannot interact with lipid rafts in presence of AmyP53. These data demonstrated that AmyP53 prevents amyloid pore formation and cellular Ca 2+ entry by competitive inhibition of Aβ 1-42 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's, Parkinson's, and related proteinopathies.
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hal-04445359 , version 1 (07-02-2024)

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Fodil Azzaz, Henri Chahinian, Nouara Yahi, Jacques Fantini, Coralie Di Scala. AmyP53 Prevents the Formation of Neurotoxic β-Amyloid Oligomers through an Unprecedent Mechanism of Interaction with Gangliosides: Insights for Alzheimer’s Disease Therapy. International Journal of Molecular Sciences, 2023, 24 (2), pp.1760. ⟨10.3390/ijms24021760⟩. ⟨hal-04445359⟩

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