PMID- 26385876
OWN - NLM
STAT- MEDLINE
DCOM- 20160722
LR  - 20200225
IS  - 1755-5949 (Electronic)
IS  - 1755-5930 (Print)
IS  - 1755-5930 (Linking)
VI  - 21
IP  - 11
DP  - 2015 Nov
TI  - Valproic Acid Modifies Synaptic Structure and Accelerates Neurite Outgrowth Via 
      the Glycogen Synthase Kinase-3beta Signaling Pathway in an Alzheimer's Disease 
      Model.
PG  - 887-97
LID - 10.1111/cns.12445 [doi]
AB  - AIM: Tau hyperphosphorylation and amyloid beta-peptide overproduction, caused by 
      altered localization or abnormal activation of glycogen synthase kinase-3beta 
      (GSK-3beta), 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-3beta (pSer9-GSK-3beta) 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. 
      CONCLUSION: VPA improves behavioral deficits in AD, modifies synaptic structure, 
      and accelerates neurite outgrowth, by inhibiting the activity of GSK-3beta, 
      decreasing hyperphosphorylated tau, enhancing CREB and BDNF expression.
CI  - (c) 2015 John Wiley & Sons Ltd.
FAU - Long, Zhi-Min
AU  - Long ZM
AD  - Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, 
      Chongqing, China.
AD  - Department of Anatomy, Chongqing Medical University, Chongqing, China.
FAU - Zhao, Lei
AU  - Zhao L
AD  - Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, 
      Chongqing, China.
FAU - Jiang, Rong
AU  - Jiang R
AD  - Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, 
      Chongqing, China.
FAU - Wang, Ke-Jian
AU  - Wang KJ
AD  - Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, 
      Chongqing, China.
AD  - Department of Anatomy, Chongqing Medical University, Chongqing, China.
FAU - Luo, Shi-Fang
AU  - Luo SF
AD  - Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, 
      Chongqing, China.
AD  - Department of Anatomy, Chongqing Medical University, Chongqing, China.
FAU - Zheng, Min
AU  - Zheng M
AD  - Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, 
      Chongqing, China.
FAU - Li, Xiao-Feng
AU  - Li XF
AD  - Department of Neurology, The 2nd Affiliated Hospital, Chongqing Medical 
      University, Chongqing, China.
FAU - He, Gui-Qiong
AU  - He GQ
AD  - Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, 
      Chongqing, China.
AD  - Department of Anatomy, Chongqing Medical University, Chongqing, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150919
PL  - England
TA  - CNS Neurosci Ther
JT  - CNS neuroscience & therapeutics
JID - 101473265
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (PSEN1 protein, human)
RN  - 0 (Presenilin-1)
RN  - 0 (tau Proteins)
RN  - 614OI1Z5WI (Valproic Acid)
RN  - EC 2.7.11.1 (GSK3B protein, human)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.7.11.1 (Gsk3b protein, mouse)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
SB  - IM
MH  - Alzheimer Disease/complications/*drug therapy/genetics/*pathology
MH  - Amyloid beta-Protein Precursor/genetics
MH  - Animals
MH  - Brain/pathology
MH  - Cells, Cultured
MH  - Enzyme Inhibitors/pharmacology/*therapeutic use
MH  - Glycogen Synthase Kinase 3/*metabolism
MH  - Glycogen Synthase Kinase 3 beta
MH  - Humans
MH  - Male
MH  - Memory Disorders/drug therapy/etiology
MH  - Mice
MH  - Mice, Transgenic
MH  - Nerve Tissue Proteins/metabolism
MH  - Neurites/*drug effects/pathology/ultrastructure
MH  - Neurons/drug effects/pathology
MH  - Presenilin-1/genetics
MH  - Signal Transduction/*drug effects/genetics
MH  - Synapses/*drug effects/pathology
MH  - Up-Regulation/drug effects/genetics
MH  - Valproic Acid/pharmacology/*therapeutic use
MH  - tau Proteins/metabolism
PMC - PMC6493017
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - GSK-3beta
OT  - Neurite
OT  - Synapse
OT  - Tau
OT  - Valproic acid
COIS- The authors declare no conflict of interest.
EDAT- 2015/09/20 06:00
MHDA- 2016/07/23 06:00
PMCR- 2015/09/19
CRDT- 2015/09/20 06:00
PHST- 2015/05/19 00:00 [received]
PHST- 2015/07/28 00:00 [revised]
PHST- 2015/07/29 00:00 [accepted]
PHST- 2015/09/20 06:00 [entrez]
PHST- 2015/09/20 06:00 [pubmed]
PHST- 2016/07/23 06:00 [medline]
PHST- 2015/09/19 00:00 [pmc-release]
AID - CNS12445 [pii]
AID - 10.1111/cns.12445 [doi]
PST - ppublish
SO  - CNS Neurosci Ther. 2015 Nov;21(11):887-97. doi: 10.1111/cns.12445. Epub 2015 Sep 
      19.