Abstract

Alzheimer's disease (AD) is undoubtedly one of the serious and growing public health challenges in the world today. There is an unmet need for new and effective preventative and therapeutic treatment approaches for AD, particularly at early stages of the disease. However, the underlying mechanism against A beta-induced electrophysiological alteration in cultured hippocampal pyramidal neurons is still not fully understood. This study investigated the impacts of activation and inhibition of PPAR-gamma/delta on the A beta-induced functional toxicity, which occured before cell death, using patch clamp technique. Findings demonstrated that A beta treatment alone altered the normal electrophysiological properties and reduced the Ca2+ channel currents in primary cultured hippocampal pyramidal neurons without any major changes either in cell structure, as evidenced by electron microscope examination, or cell viability. Rosiglitazone (30 mu M), a potent PPAR-gamma activator, when co-treated with A beta (100 nM) prevented almost completely the induction of function toxicity of A beta, as evidentiated by restored normal appearing electrophysiological properties. Inhibition of PPAR- gamma/delta by FH535 (15 mu M), an inhibitor of both Wnt/beta-catenin signaling and PPAR-gamma and delta activity, when applied in combination of A beta not only worsen the toxic electrophysiological effects of A beta on firing frequency, membrane resistance and cell viability, but also even preserved the suppressive effect of A beta on Ca2+ channel current when compared to control condition. Overall, these findings suggest that PPAR-gamma activation could be a potential candidate to prevent the functional changes induced by low concentration of A beta which may possibly occur in neurons during early stages of AD.