title: Atorvastatin prevents Aβ oligomer-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting Tau cleavage.
abstract: OBJECTIVE
  The proteolytic cleavage of Tau is involved in Aβ-induced neuronal dysfunction and cell death. In this study, we investigated whether atorvastatin could prevent Tau cleavage and hence prevent Aβ1-42 oligomer (AβO)-induced neurotoxicity in cultured cortical neurons.
  
  
  METHODS
  Cultured rat hippocampal neurons were incubated in the presence of AβOs (1.25 μmol/L) with or without atorvastatin pretreatment. ATP content and LDH in the culture medium were measured to assess the neuronal viability. Caspase-3/7 and calpain protease activities were detected. The levels of phospho-Akt, phospho-Erk1/2, phospho-GSK3β, p35 and Tau proteins were measured using Western blotting.
  
  
  RESULTS
  Treatment of the neurons with AβO significantly decreased the neuronal viability, induced rapid activation of calpain and caspase-3/7 proteases, accompanied by Tau degradation and relatively stable fragments generated in the neurons. AβO also suppressed Akt and Erk1/2 kinase activity, while increased GSK3β and Cdk5 activity in the neurons. Pretreatment with atorvastatin (0.5, 1, 2.5 μmol/L) dose-dependently inhibited AβO-induced activation of calpain and caspase-3/7 proteases, and effectively diminished the generation of Tau fragments, attenuated synaptic damage and increased neuronal survival. Atorvastatin pretreatment also prevented AβO-induced decreases in Akt and Erk1/2 kinase activity and the increases in GSK3β and Cdk5 kinase activity.
  
  
  CONCLUSIONS
  Atorvastatin prevents AβO-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting calpain- and caspase-mediated Tau cleavage.
authors.affiliation: Department of Pharmacology, Liaoning Medical University, Jinzhou 121001, China.
authors.forename: Hai-juan
authors.initials: HJ
authors.lastname: Sui
authors.affiliation: Department of Pharmacology, Liaoning Medical University, Jinzhou 121001, China.
authors.forename: Ling-ling
authors.initials: LL
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Liaoning Medical University, Jinzhou 121001, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Liaoning Medical University, Jinzhou 121001, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D000069059:Atorvastatin / Q000494:pharmacology*; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000633:toxicity*; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology; D059748:Proteolysis; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D061945:Caspase Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C489131:Mapt protein, rat; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011480:Protease Inhibitors; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D000069059:Atorvastatin; D051360:Cyclin-Dependent Kinase 5; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; C495907:Cdk5 protein, rat; D038362:Glycogen Synthase Kinase 3; D002154:Calpain; C505410:Casp3 protein, rat; D053148:Caspase 3; D053179:Caspase 7