期刊
NEUROPHARMACOLOGY
卷 97, 期 -, 页码 122-132出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2015.05.020
关键词
Simvastatin (SV); beta-Amyloid (A beta); Neurogenesis; alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR); Farnesyl pyrophosphate (FPP)
资金
- National 973 Basic Research Program of China [2014CB943303]
- National Natural Science Foundation of China [31171440, 81361120247, 81471157]
Simvastatin (SV) is reported to improve cognition and slow progression of Alzheimer's disease (AD), however underlying mechanism still remains unclear. In hippocampal dentate gyrus (DG), beta-amyloid (A beta) selectively impairs survival and neurite growth of newborn neurons in the 2nd week after birth. The aim of this study was to examine the effects of SV on the impairment of neurogenesis and the spatial cognitive deficits in A(beta 25-35) (3 nmol)-injected (i.c.v.) mice (A(beta 25-35)-mice). Herein, we reported that the SV-treatment (20 mg/kg) on days 2-14 after BrdU-injection could dose-dependently protect the survival and neurite growth of newborn neurons, which was blocked by the alpha 7nAChR antagonist MLA or the famesol (FOH) that can convert to farnesyl pyrophosphate (FPP), but not the alpha 4 beta 2nAChR antagonist DHOE. The SV-treatment in A beta(25-35)-mice rescued the decline of Akt phosphorylation and increased the ERK1/2 phosphorylation in hippocampus, which was sensitive to MLA and FOH. The PI3K inhibitor LY294002 could abolish the SV-protected neurogenesis in A(beta 25-35)-mice, but the MEK inhibitor U0126 had no effects. The SV-treatment could correct the decline of hippocampal BDNF concentration in A beta 25 -35-mice, which was blocked by MLA and FOH. Using Morris water maze and Y-maze tasks, we further observed that the SV-treatment in A(beta 25-35)-mice could improve their spatial cognitive deficits, which was sensitive to the application of FOH. The results indicate that the SV-treatment in A(beta 25-35)-mice via reduction of FPP can protect neurogenesis through alpha 7nAChR-cascading PI3K-Akt and increasing BDNF, which may improve spatial cognitive function. (C) 2015 Elsevier Ltd. All rights reserved.
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