title: Collaboration of geldanamycin-activated P70S6K and Hsp70 against beta-amyloid-induced hippocampal apoptosis: an approach to long-term memory and learning.
abstract: One of the neuropathological hallmarks of Alzheimer's disease (AD) is the accumulation of beta-amyloid peptides (Aβ) in senile plaques. Aβ-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 Aβ (1-42) in CA1 area of hippocampus. The learning and memory of the rats were assessed 7 days after injection of Aβ using passive avoidance (PA) task. As potential contributing factors in Aβ-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 Aβ-injected rats. Our behavioral data suggest that GA pretreatment can significantly suppress memory deficits in Aβ-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 Aβ (1-42) toxicity and memory deficits, at least in part, by upregulating of Hsp70 and P70S6K.
authors.affiliation: NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Nayereh
authors.initials: N
authors.lastname: Zare
authors.forename: Fereshteh
authors.initials: F
authors.lastname: Motamedi
authors.forename: Hadi
authors.initials: H
authors.lastname: Digaleh
authors.forename: Fariba
authors.initials: F
authors.lastname: Khodagholi
authors.forename: Nader
authors.initials: N
authors.lastname: Maghsoudi
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008297:Male; D057567:Memory, Long-Term / Q000187:drug effects*; D010446:Peptide Fragments / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; C075222:amyloid beta-protein (1-42); D051028:bcl-2-Associated X Protein; D011065:Poly(ADP-ribose) Polymerases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D053148:Caspase 3; D005978:Glutathione; C001277:geldanamycin