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Valproic Acid Modifies Synaptic Structure and Accelerates Neurite Outgrowth Via the Glycogen Synthase Kinase-3β Signaling Pathway in an Alzheimer's Disease Model.
CNS Neurosci Ther. 2015 Nov; 21(11):887-97.CN

Abstract

AIM

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.

CONCLUSION

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.

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Authors+Show Affiliations

Long ZM
Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China. Department of Anatomy, Chongqing Medical University, Chongqing, China.
Zhao L
Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China.
Jiang R
Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, China.
Wang KJ
Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China. Department of Anatomy, Chongqing Medical University, Chongqing, China.
Luo SF
Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China. Department of Anatomy, Chongqing Medical University, Chongqing, China.
Zheng M
Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, China.
Li XF
Department of Neurology, The 2nd Affiliated Hospital, Chongqing Medical University, Chongqing, China.
He GQ
Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China. Department of Anatomy, Chongqing Medical University, Chongqing, China.

MeSH

Alzheimer DiseaseAmyloid beta-Protein PrecursorAnimalsBrainCells, CulturedEnzyme InhibitorsGlycogen Synthase Kinase 3Glycogen Synthase Kinase 3 betaHumansMaleMemory DisordersMiceMice, TransgenicNerve Tissue ProteinsNeuritesNeuronsPresenilin-1Signal TransductionSynapsesUp-RegulationValproic Acidtau Proteins

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26385876

Citation

Long, Zhi-Min, et al. "Valproic Acid Modifies Synaptic Structure and Accelerates Neurite Outgrowth Via the Glycogen Synthase Kinase-3β Signaling Pathway in an Alzheimer's Disease Model." CNS Neuroscience & Therapeutics, vol. 21, no. 11, 2015, pp. 887-97.
Long ZM, Zhao L, Jiang R, et al. Valproic Acid Modifies Synaptic Structure and Accelerates Neurite Outgrowth Via the Glycogen Synthase Kinase-3β Signaling Pathway in an Alzheimer's Disease Model. CNS Neurosci Ther. 2015;21(11):887-97.
Long, Z. M., Zhao, L., Jiang, R., Wang, K. J., Luo, S. F., Zheng, M., Li, X. F., & He, G. Q. (2015). Valproic Acid Modifies Synaptic Structure and Accelerates Neurite Outgrowth Via the Glycogen Synthase Kinase-3β Signaling Pathway in an Alzheimer's Disease Model. CNS Neuroscience & Therapeutics, 21(11), 887-97. https://doi.org/10.1111/cns.12445
Long ZM, et al. Valproic Acid Modifies Synaptic Structure and Accelerates Neurite Outgrowth Via the Glycogen Synthase Kinase-3β Signaling Pathway in an Alzheimer's Disease Model. CNS Neurosci Ther. 2015;21(11):887-97. PubMed PMID: 26385876.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Valproic Acid Modifies Synaptic Structure and Accelerates Neurite Outgrowth Via the Glycogen Synthase Kinase-3β Signaling Pathway in an Alzheimer's Disease Model. AU - Long,Zhi-Min, AU - Zhao,Lei, AU - Jiang,Rong, AU - Wang,Ke-Jian, AU - Luo,Shi-Fang, AU - Zheng,Min, AU - Li,Xiao-Feng, AU - He,Gui-Qiong, Y1 - 2015/09/19/ PY - 2015/05/19/received PY - 2015/07/28/revised PY - 2015/07/29/accepted PY - 2015/9/20/entrez PY - 2015/9/20/pubmed PY - 2016/7/23/medline KW - Alzheimer's disease KW - GSK-3β KW - Neurite KW - Synapse KW - Tau KW - Valproic acid SP - 887 EP - 97 JF - CNS neuroscience & therapeutics JO - CNS Neurosci Ther VL - 21 IS - 11 N2 - AIM: 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. CONCLUSION: 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. SN - 1755-5949 UR - https://www.unboundmedicine.com/medline/citation/26385876/Valproic_Acid_Modifies_Synaptic_Structure_and_Accelerates_Neurite_Outgrowth_Via_the_Glycogen_Synthase_Kinase_3β_Signaling_Pathway_in_an_Alzheimer's_Disease_Model_ DB - PRIME DP - Unbound Medicine ER -