Collaboration of geldanamycin-activated P70S6K and Hsp70 against beta-amyloid-induced hippocampal apoptosis: an approach to long-term memory and learning

One of the neuropathological hallmarks of Alzheimer's disease (AD) is the accumulation of beta-amyloid peptides (A beta) in senile plaques. A beta-induced oxidative stress is believed to be responsible for degeneration and apoptosis of neurons and consequent cognitive and memory deficits. Here, we investigated the possible neuroprotective effect of the heat shock protein 90 (Hsp90) inhibitor geldanamycin (GA) against amyloid pathogenesis in adult male Wistar rats. GA or vehicle was injected into the lateral cerebral ventricles of rats 24 h before injection of A beta (1-42) in CA1 area of hippocampus. The learning and memory of the rats were assessed 7 days after injection of A beta using passive avoidance (PA) task. As potential contributing factors in A beta-induced memory decline, we evaluated apoptotic markers and also used terminal-transferase UTP nick end labeling (TUNEL) technique to detect apoptosis in the hippocampus of A beta-injected rats. Our behavioral data suggest that GA pretreatment can significantly suppress memory deficits in A beta-injected rats. There was also not only a marked increase in Hsp70 level but also upregulated 70 kDa ribosomal protein S6 kinase (p70S6K) in the hippocampus of GA-treated groups with a reduction in apoptotic factors including caspase-3, poly (ADP-ribose) polymerase, Bax/Bcl-2 ratio, and TUNEL-positive cells as well. Thus, we conclude that GA exerts its protective effects against A beta (1-42) toxicity and memory deficits, at least in part, by upregulating of Hsp70 and P70S6K.