Oxidative stress resistance in hippocampal cells is associated with altered membrane fluidity and enhanced nonamyloidogenic cleavage of endogenous amyloid precursor protein.

Reactive oxygen species (ROS) have important roles as signaling molecules in the regulation of a variety of biological processes. On the other hand, chronic oxidative stress exerted by ROS is widely considered a causative factor in aging. Therefore, cells need to be able to adapt to a chronic oxidative challenge and do so to a certain cell-type-specific extent. Recently, we have shown in oxidative-stress-resistant cell lines, HT22(H2O2) and HT22(Glu), derived from the neuronal cell line HT22 by chronic exposure to sublethal concentrations of H(2)O(2) and glutamate, that, in addition to the known antioxidant defense mechanisms, e.g., activation of antioxidant enzymes or up-regulation of heat-shock proteins, oxidative stress resistance depends on the composition of cellular membranes. Here, we extend our previous investigations and report increased membrane fluidity in HT22(H2O2) and HT22(Glu) cells compared to the parental HT22(WT) cells. The increased membrane fluidity correlates with a redistribution of cholesterol, sphingomyelin, and membrane-associated proteins involved in APP processing between detergent-resistant and detergent-soluble membrane subdomains. The altered membrane properties were associated with drastic changes in the metabolism of the Alzheimer disease-associated amyloid precursor protein (APP), particularly toward enhanced production of soluble APP alpha, which is a known neuroprotective factor. Thus our -data provide a link between chronic oxidative stress, alterations in membrane fluidity and composition of membrane subdomains, stress adaptation, and APP processing.