title: Dose-Dependent Neuroprotection and Neurotoxicity of Simvastatin through Reduction of Farnesyl Pyrophosphate in Mice Treated with Intracerebroventricular Injection of Aβ 1-42.
abstract: BACKGROUND
  Simvastatin (SV) has been reported to improve dementia and slow progression of Alzheimer's disease (AD), however there are conflicting reports.
  
  
  OBJECTIVE
  Intracerebroventricular injection of aggregated Aβ1-42 in mice (Aβ1-42-mice) caused spatial cognitive deficits, long-term potentiation (LTP) impairment, and death of hippocampal pyramidal cells. The present study focused on exploring the dose-dependent effects of SV (10-80 mg/kg) on Aβ1-42-impaired spatial memory and the underlying mechanisms.
  
  
  RESULTS
  The treatment of Aβ1-42-mice with SV for continuous 15 days could attenuate the spatial cognitive deficits and recover the LTP induction in a "U" type dose-dependent manner. The death of pyramidal cells in Aβ1-42-mice was significantly reduced by the SV-treatment at 20 mg/kg, but not at a dose of 10 or 40 mg/kg, even was aggravated at a dose of 80 mg/kg. Hippocampal NMDA receptor (NMDAr) NR2B phosphorylation (phospho-NR2B) was elevated in Aβ1-42-mice, which was further dose-dependently increased by SV-treatment. Replenishment of isoprenoid farnesyl pyrophosphate (FPP) by applying farnesol (FOH) could abolish the SV-increased phospho-NR2B in Aβ1-42-mice, but had no effect on the Aβ1-42-enhanced phospho-NR2B. NMDAr antagonist blocked the neurotoxicity of Aβ1-42 and SV (80 mg/kg) in Aβ1-42-mice, whereas FOH only inhibited SV (80 mg/kg)-neurotoxicity. The SV-treatment in Aβ1-42-mice corrected the decrease in hippocampal Akt phosphorylation. The PI3K inhibitor abolished the SV (20 mg/kg)-neuroprotection in Aβ1-42-mice.
  
  
  CONCLUSIONS
  SV-treatment in Aβ1-42-mice exerts dose-dependent neuroprotection and neurotoxicity by reducing FPP to enhance the phosphorylation of NR2B and Akt.
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, China.|Department of Neurology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.|Department of Physiology, Nanjing Medical University, Nanjing, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, China.
authors.forename: Guoxi
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, China.
authors.forename: Conghui
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, China.
authors.forename: Baofeng
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, China.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Sha
authors.affiliation: Department of Neurology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wan
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.|Department of Physiology, Nanjing Medical University, Nanjing, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011106:Polyisoprenyl Phosphates / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012717:Sesquiterpenes / Q000378:metabolism*; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*; D065852:Spatial Memory / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011106:Polyisoprenyl Phosphates; D016194:Receptors, N-Methyl-D-Aspartate; D012717:Sesquiterpenes; C075222:amyloid beta-protein (1-42); C004808:farnesyl pyrophosphate; D019821:Simvastatin
keywords: Amyloid–β 1–42; NMDA receptor; hippocampus; long-term potentiation; memory; simvastatin