Dose-Dependent Neuroprotection and Neurotoxicity of Simvastatin through Reduction of Farnesyl Pyrophosphate in Mice Treated with Intracerebroventricular Injection of Aβ 1-42
Affiliations: [a] State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China | [b] Department of Physiology, Nanjing Medical University, Nanjing, China | [c] Department of Neurology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Correspondence:
[*]
Correspondence to: Ling Chen, PhD, MD, Laboratory of Reproductive Medicine, Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing, China. Tel.: +86 25 86862878; Fax: +86 25 86262878; E-mail: [email protected].
Correspondence:
[*]
Correspondence to: Qi Wan, PhD, MD, Department of Neurology, First Affiliated Hospital of Nanjing Medical University, Guangzhou Road 300,Nanjing 210029, China. Tel.: +86 25 83714511; Fax: +86 25 86260332; E-mail: [email protected].
Abstract: Background:Simvastatin (SV) has been reported to improve dementia and slow progression of Alzheimer’s disease (AD), however there are conflicting reports. Objective & Methods: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. Conclusion:SV-treatment in Aβ1-42-mice exerts dose-dependent neuroprotection and neurotoxicity by reducing FPP to enhance the phosphorylation of NR2B and Akt.
