title: Valproic Acid Modifies Synaptic Structure and Accelerates Neurite Outgrowth Via the Glycogen Synthase Kinase-3β Signaling Pathway in an Alzheimer's Disease Model.
abstract: OBJECTIVE
  Tau hyperphosphorylation and amyloid β-peptide overproduction, caused by altered localization or abnormal activation of glycogen synthase kinase-3β (GSK-3β), is a pathogenic mechanism in Alzheimer's disease (AD). Valproic acid (VPA) attenuates senile plaques and neuronal loss. Here, we confirmed that VPA treatment improved spatial memory in amyloid precursor protein (APP)/presenilin 1 (PS 1) double-transgenic mice and investigated the effect of VPA on synaptic structure and neurite outgrowth.
  
  
  METHODS
  We used ultrastructural analysis, immunocytochemistry, immunofluorescence staining, and Western blot analysis to assess the effect of VPA treatment in mice.
  
  
  RESULTS
  VPA treatment thickened the postsynaptic density, increased the number of presynaptic vesicles, and upregulated the expression of synaptic markers PSD-95 and GAP43. VPA increased neurite length of hippocampal neurons in vivo and in vitro. In VPA-treated AD mouse brain, inactivated GSK-3β (pSer9-GSK-3β) was markedly increased, while hyperphosphorylation of tau at Ser396 and Ser262 was decreased; total tau levels remained similar. VPA treatment notably improved pSer133-cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) levels, which are associated with synaptic function and neurite outgrowth.
  
  
  CONCLUSIONS
  VPA improves behavioral deficits in AD, modifies synaptic structure, and accelerates neurite outgrowth, by inhibiting the activity of GSK-3β, decreasing hyperphosphorylated tau, enhancing CREB and BDNF expression.
authors.affiliation: Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China.|Department of Anatomy, Chongqing Medical University, Chongqing, China.
authors.forename: Zhi-Min
authors.initials: ZM
authors.lastname: Long
authors.affiliation: Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Jiang
authors.affiliation: Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China.|Department of Anatomy, Chongqing Medical University, Chongqing, China.
authors.forename: Ke-Jian
authors.initials: KJ
authors.lastname: Wang
authors.affiliation: Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China.|Department of Anatomy, Chongqing Medical University, Chongqing, China.
authors.forename: Shi-Fang
authors.initials: SF
authors.lastname: Luo
authors.affiliation: Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Department of Neurology, The 2nd Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Li
authors.affiliation: Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China.|Department of Anatomy, Chongqing Medical University, Chongqing, China.
authors.forename: Gui-Qiong
authors.initials: GQ
authors.lastname: He
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000473:pathology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016501:Neurites / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013569:Synapses / Q000187:drug effects* / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016875:tau Proteins; D014635:Valproic Acid; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: Alzheimer's disease; GSK-3β; Neurite; Synapse; Tau; Valproic acid