Lipid Dynamics in the Amyloid Cascade Hypothesis: Evaluating the Biological Relevance of In Vitro Models

This review explores the role of misfolded protein aggregates in disrupting cell membranes, a key mechanism of cytotoxicity in proteinopathies. The lipid-chaperone hypothesis (LCH) suggests that the dynamic equilibrium between lipids and lipid vesicles, governed by critical micellar concentration, should be considered when linking protein misfolding and aggregation to membrane damage. Despite the success of LCH in model systems, observing these processes in living cells is challenging due to their complex environments, which can introduce confounding variables. To fill this gap, we examine various physiopathological factors that influence the concentration of free lipids in cellular aqueous solutions, including lipid chain length, oxidative modifications, enzyme-mediated degradation, and pathological lipid dysmetabolism, all while accounting for the accumulation of misfolded proteins which is related to the onset of the diseases. This comprehensive analysis aims to provide a unified framework for understanding the cascade of molecular events connecting protein misfolding, aggregation, membrane damage, and resultant cytotoxicity.