Two-step mechanism of membrane disruption by A? through membrane fragmentation and pore formation.

ABSTRACT: Disruption of cell membranes by A? is believed to be one of the key components of A? toxicity. However, the mechanism by which this occurs is not fully understood. Here, we demonstrate that membrane disruption by A? occurs by a two-step process, with the initial formation of ion-selective pores followed by nonspecific fragmentation of the lipid membrane during amyloid fiber formation. Immediately after the addition of freshly dissolved A?(1-40), defects form on the membrane that share many of the properties of A? channels originally reported from single-channel electrical recording, such as cation selectivity and the ability to be blockaded by zinc. By contrast, subsequent amyloid fiber formation on the surface of the membrane fragments the membrane in a way that is not cation selective and cannot be stopped by zinc ions. Moreover, we observed that the presence of ganglioside enhances both the initial pore formation and the fiber-dependent membrane fragmentation process. Whereas pore formation by freshly dissolved A?(1-40) is weakly observed in the absence of gangliosides, fiber-dependent membrane fragmentation can only be observed in their presence. These results provide insights into the toxicity of A? and may aid in the design of specific compounds to alleviate the neurodegeneration of Alzheimer's disease.

SUBMITTER: Sciacca MF 

PROVIDER: S-EPMC3443794 | biostudies-other | 2012 Aug

REPOSITORIES: biostudies-other