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

Abstract

A broad range of data identify Ca2+-permeable amyloid pores as the most neurotoxic species of Alzheimer’s β-amyloid peptide (Aβ1–42). 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 Aβ1–42 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 Aβ1–42 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 Aβ1–42 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.

Host Membranes as Drivers of Virus Evolution

“…It is therefore essential that the raft is not a rigid structure but on the contrary, a malleable entity capable of offering the hydrogen bond-forming residues of the NTD many possibilities to reach the donor or acceptor atoms and form high energy hydrogen bonds. This conformational plasticity of lipid rafts has been shown by molecular modeling in the case of amyloid proteins [ 49 ]. Our team also highlighted it for viruses, as explained in Figure 8 .…”

“…In this mechanism, cholesterol exerts a kinetic effect by accelerating the binding of viruses to raft gangliosides. This process applies to viruses, but also to amyloid proteins which interact with the plasma membrane of brain cells at the level of lipid rafts, while also taking advantage of the particular properties of the ganglioside-cholesterol couple [ 49 ].…”

What Is life? Rethinking Biology in Light of Fundamental Parameters

“…Our group has applied this concept to explain how a virus is attracted by a ganglioside-enriched lipid raft on the plasma membrane of a host cell [ 32 , 33 , 34 ] and how amyloid proteins form oligomeric channels in neuronal membranes [ 35 , 36 ]. This mechanism, which is at the origin of the concentrating effect of biological membranes, requires fine tuning.…”

Lipid rafts and human diseases: why we need to target gangliosides

“…For geometrical reasons, this may occur preferentially at the edge of a lipid raft, or even outside a lipid raft if a single ganglioside is extracted from the raft by the protein with which it will form a stabilized complex. A representative example is given by synaptotagmin, a synaptic vesicle protein that acts as a plasma membrane receptor for botulinum toxin B accommodate this loop, as it would be the case at the edge of a lipid raft but not in more central areas [22]. Thus, it is at the edge of a lipid raft that gangliosidedependent membrane insertion processes generally occur.…”