Amyloid β-protein fragment 25-35 down-regulates PI3K/Akt /p70S6K pathway in rat hippocampus in vivo / 中国药理学与毒理学杂志

ABSTRACT

AIM To investigate whether Aβ deposit in Alzheimer disease(AD) impairs signal transduction pathway responsible for neuronal survival.METHODSThe rats were randomly divided into six groupscontrol group and Aβ25-35 group,Aβ25-35+ibuprofen groups (7.5 and 15 mg·kg-1,respectively),Aβ25-35+ibuprofen+LY294002 group,and Aβ25-35+LY294002 group.Rats were given ibuprofen (7.5 and 15 mg·kg-1 daily,ig) for 3 weeks prior to and 1 week after icv single dose of Aβ25-35 (10 μL,1 mmol·L-1).LY294002 was injected icv 1 h before the injection of Aβ25-35.Seven days after Aβ25-35 injection,the hippocampal expressions of P53,Bax,Fas ligand (FasL),Bcl-2 proteins,phospho-Akt/PKB,and phosphorylated 70 ku ribosomal protein S6 kinase (p70S6K) and caspase 3 were determined in the brain tissue preparations from CA1 area with Western blot.The activity of caspase 3 was measured using a caspase 3 colorimetric activity assay kit.RT-PCR was used to show the change of p70s6k mRNA level.RESULTS Aβ25-35 icv injection significantly down-regulated phosphorylated Akt/PKB from 1.32±0.14 to 0.69±0.08 and p70S6K from 0.769±0.028 to 0.479±0.032 in hippocampal CA1 region.These changes were accompanied by increased expressions of the proapoptotic proteins P53,Bax,and FasL and decreased expression of the anti-apoptotic protein Bcl-2 in rat hippocampus.In addition,caspase 3 activity was significantly enhanced in hippocampal CA1 region in Aβ25-35-treated rats compared with control rats.Ibuprofen can reverse these Aβ25-35-induced changes.CONCLUSION Down-regulated anti-apoptotic PI3K/Akt/p70S6K signaling pathway induced by Aβ25-35 in rat hippocampus may contribute to the neuronal damage in AD.Ibuprofen prevents Aβ25-35-induced down-regulation of PI3K/Akt/p70S6K signaling pathway.