Cooperative dissolution of peptidomimetic vesicles and amyloid β fibrils

Abstract

The aggregation of amyloid proteins in the brain is a significant neurotoxic event that contributes to neurodegenerative disorders. The aggregation of amyloid beta (Aβ), particularly Aβ42 monomers, into various forms such as oligomers, protofibrils, fibrils, and amyloid plaques is a key pathological feature in Alzheimer's disease. As a result, Aβ42 is a primary target and the development of molecular strategies for the dissolution of Aβ42 aggregates is considered a promising approach to mitigating Alzheimer's disease pathology. A set of pyrene-conjugated peptidomimetics derived from Aβ14-23 (Akd^cPy, Akd^mPy, and AkdⁿPy) by incorporating an unnatural amino acid [kd: cyclo(Lys-Asp)] were studied for their ability to modulate Aβ42 aggregation. Akd^cPy and Akd^mPy formed vesicular structures in aqueous media. The vesicles of Akd^mPy loaded with the neuroprotective compound berberine (Ber), dissipated mutually in the presence of preformed Aβ42 fibrils. During this process, the active drug Ber was released. This work is expected to inspire the development of drug-loaded peptidomimetic-based therapeutic formulations to modulate disorders associated with amyloid toxicity.