Aggregation of Alzheimer's amyloid ß-peptide in biological membranes: a molecular dynamics study.

ABSTRACT

Numerous studies have concluded that the interaction of the amyloid ß-peptide (Aß) and cellular membranes contributes to the toxicity and cell death observed in the progression of Alzheimer's disease. Aggregated Aß species disrupt membranes, leading to physical instability and ion leakage. Further, the presence of Aß on the membrane surface increases the aggregation rate of the peptide, as diffusion occurs in two dimensions, increasing the probability of interpeptide interactions. Molecular dynamics (MD) simulations have been used to investigate Aß in a number of environments, including aqueous solution and membranes. We previously showed that monomeric Aß40 remains embedded in membranes composed of the most common lipids found in the cell membrane, but that the presence of ganglioside GM1 promotes release of the peptide into the extracellular medium. Here, we explore the interactions of two Aß40 peptides in model membranes to understand whether aggregation can occur prior to the release of the peptide into the aqueous environment. We found that aggregation occurred, to different extents, in each of the model membranes and that the aggregates, once formed, did not exit the membrane environment. This information may have important implications for understanding the affinity of Aß for membranes and the mechanism of Aß toxicity in Alzheimer's disease.