title: Simvastatin prevents β-amyloid(25-35)-impaired neurogenesis in hippocampal dentate gyrus through α7nAChR-dependent cascading PI3K-Akt and increasing BDNF via reduction of farnesyl pyrophosphate.
abstract: 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), β-amyloid (Aβ) selectively impairs survival and neurite growth of newborn neurons in the 2(nd) 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 Aβ25-35 (3 nmol)-injected (i.c.v.) mice (Aβ25-35-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 α7nAChR antagonist MLA or the farnesol (FOH) that can convert to farnesyl pyrophosphate (FPP), but not the α4β2nAChR antagonist DHβE. The SV-treatment in Aβ25-35-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 Aβ25-35-mice, but the MEK inhibitor U0126 had no effects. The SV-treatment could correct the decline of hippocampal BDNF concentration in Aβ25-35-mice, which was blocked by MLA and FOH. Using Morris water maze and Y-maze tasks, we further observed that the SV-treatment in Aβ25-35-mice could improve their spatial cognitive deficits, which was sensitive to the application of FOH. The results indicate that the SV-treatment in Aβ25-35-mice via reduction of FPP can protect neurogenesis through α7nAChR-cascading PI3K-Akt and increasing BDNF, which may improve spatial cognitive function.
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Conghui
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Guoxi
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Libin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Sha
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China; State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China. Electronic address: lingchen@njmu.edu.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D018891:Dentate Gyrus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008813:Mice, Inbred ICR; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012717:Sesquiterpenes / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; D064569:alpha7 Nicotinic Acetylcholine Receptor; C074636:amyloid beta-protein (25-35); C004808:farnesyl pyrophosphate; D019821:Simvastatin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Farnesyl pyrophosphate (FPP); Neurogenesis; Simvastatin (SV); α7 nicotinic acetylcholine receptor (α7nAChR); β-Amyloid (Aβ)