Membrane cholesterol enrichment prevents Aβ-induced oxidative stress in Alzheimer's fibroblasts

A growing body of evidence Implicates low membrane cholesterol in the pathogenesis of Alzheimer's disease (AD). Here we show that A beta 42 soluble oligomers accumulate more slowly and in reduced amount at the plasma membranes of PS-1L392V and APPV7171 fibroblasts from familial AD (FAD) patients enriched in cholesterol content than at the counterpart membranes. The A beta 42-induced production of reactive oxygen species (ROS) and the increase in membrane lipoperoxidation were also prevented by high membrane cholesterol, thus resulting in a higher resistance to amyloid toxicity with respect to control fibroblasts. On the other hand, the recruitment of amyloid assemblies to the plasma membrane of cholesterol-depleted fibroblasts was significantly increased, thus triggering an earlier and sharper production of ROS and a higher membrane oxidative injury. These results identify membrane cholesterol as being key to A beta 42 oligomer accumulation at the cell surfaces and to the following A beta 42-induced cell death in AD neurons. (C) 2009 Elsevier Inc. All rights reserved.