MISFOLDING AND EARLY AGGREGATION OF AMYLOID β42 PROTEIN: THE CRITICAL ROLE OF MEMBRANES

Abstract

Even with growing evidence for the involvement of Aβ oligomers in the development of Alzheimer's disease (AD), very limited knowledge exists regarding the molecular mechanisms behind the protein aggregation processes for Aβ. The amyloid cascade hypothesis posits that the onset of diseases due to protein aggregation involves the spontaneous assembly of an amyloidogenic polypeptide. However, there is a serious complication with translating current knowledge on amyloid aggregation in vitro to understanding the aggregation process in vivo. We combined AFM imaging and high-power computational approaches to elucidate a molecular mechanism of aggregation of Aβ42 on membranes. We have discovered that interaction of Aβ42 with membranes allows for Aβ42 to assemble in oligomers at the physiological concentration range. We were able to directly visualize a spontaneous assembly of Aβ42 aggregates on the membrane bilayers. Importantly, this aggregation process is dynamic, so the assembled aggregates can dissociate from the surface into the bulk solution and play roles of seeds for aggregation in the bulk solution, or start a neurotoxic effect such as phosphorylation of the tau protein to initiate its misfolding and aggregation. To elucidate a molecular mechanism underlying the on-surface aggregation process, we applied computational modeling (all-atom Molecular Dynamic simulations). The simulations demonstrate that the interaction with the membrane surface dramatically changes the conformation of Aβ42 protein allowing for the formation of long aggregation–prone β-sheet structures never observed for Aβ42 protein in solution. We posit that on-membrane aggregation is the mechanism by which neurotoxic amyloid aggregates are assembled under physiological conditions. We propose a model in which amyloid aggregation is linked with elevated synthesis of amyloid proteins. A change in membrane properties leading to an increase in affinity of amyloid proteins to the membrane surface facilitates the assembly of stable oligomers. The proposed model is a significant departure from the current model as it directs the development of treatments and preventions towards approaches that control the cell membranes composition to prevent the on-surface aggregation process.