Amyloid cascade hypothesis for Alzheimer’s disease. Does it work under physiological conditions?

Abstract

<img src=” https://s3.amazonaws.com/production.scholastica/article/77826/large/prnano_942023_toc_figure.jpg?1686262046”> Plaques in the brain consisting of proteins are a hallmark of diseases like Alzheimer’s disease (AD) and Parkinson’s disease (PD). Such aggregates can be assembled spontaneously by specialized proteins such as amyloid beta (A β) proteins in the case of AD. Numerous in vitro studies made a foundation for the Amyloid Cascade Hypothesis (ACH), according to which the misfolding of proteins leads to their self-assembly into toxic oligomers along with the formation of amyloid fibrils assembled as plaques in the brain. Notably physiological concentration of A β proteins in the brain is in the low nanomolar concentration, so no spontaneous aggregation of A β protein occurs at such conditions, questioning the validity of the ACH model. However, recent studies revealed that surfaces could play a role as a catalyst of the aggregation process, so self-assembly of A β can be observed at physiologically low concentrations of A β proteins, although no spontaneous aggregation occurs in the bulk solution. The catalytic property of membrane surfaces towards A β aggregation depends on the membrane composition. This finding suggests a number of novel ideas on molecular mechanisms of amyloid self-assembly, which lay a foundation for the development of treatments and preventions for AD, as discussed in this article.