Synaptotoxicity of Alzheimer beta amyloid can be explained by its membrane perforating property

Abstract

The mechanisms that induce Alzheimer's disease (AD) are largely unknown thereby deterring the development of diseasemodifying therapies. One working hypothesis of AD is that Aβ excess disrupts membranes causing pore formation leading to alterations in ionic homeostasis. However, it is largely unknown if this also occurs in native brain neuronal membranes. Here we show that similar to other pore forming toxins, Ab induces perforation of neuronal membranes causing an increase in membrane conductance, intracellular calcium and ethidium bromide influx. These data reveal that the target of Ab is not another membrane protein, but that Ab itself is the cellular target thereby explaining the failure of current therapies to interfere with the course of AD. We propose that this novel effect of Ab could be useful for the discovery of anti AD drugs capable of blocking these "Aβb perforates". In addition, we demonstrate that peptides that block Aβ neurotoxicity also slow or prevent the membrane-perforating action of Aβ. © 2010 Sepulveda et al.