  Over the past thirty years, researchers have highlighted the role played by a
class of proteins or polypeptides that forms pathogenic amyloid aggregates in
vivo, including i) the amyloid Abeta peptide, which is known to form senile
plaques in Alzheimer's disease; ii) alpha-synuclein, responsible for Lewy body
formation in Parkinson's disease and iii) IAPP, which is the protein component
of type 2 diabetes-associated islet amyloids. These proteins, known as
intrinsically disordered proteins (IDPs), are present as highly dynamic
conformational ensembles. IDPs can partially (mis) fold into (dys) functional
conformations and accumulate as amyloid aggregates upon interaction with other
cytosolic partners such as proteins or lipid membranes. In addition, an
increasing number of reports link the toxicity of amyloid proteins to their
harmful effects on membrane integrity. Still, the molecular mechanism
underlying the amyloidogenic proteins transfer from the aqueous environment to
the hydrocarbon core of the membrane is poorly understood. This review starts
with a historical overview of the toxicity models of amyloidogenic proteins to
contextualize the more recent lipid-chaperone hypothesis. Then, we report the
early molecular-level events in the aggregation and ion-channel pore formation
of Abeta, IAPP, and alpha-synuclein interacting with model membranes,
emphasizing the complexity of these processes due to their different
spatial-temporal resolutions. Next, we underline the need for a combined
experimental and computational approach, focusing on the strengths and
weaknesses of the most commonly used techniques. Finally, the last two chapters
highlight the crucial role of lipid-protein complexes as molecular switches
among ion-channel-like formation, detergent-like, and fibril formation
mechanisms and their implication in fighting amyloidogenic diseases.
