Valproic Acid Modifies Synaptic Structure and Accelerates Neurite Outgrowth Via the Glycogen Synthase Kinase-3β Signaling Pathway in an Alzheimer's Disease Model

Autor:	Zhimin Long, Xiao-Feng Li, Guiqiong He, Lei Zhao, Kejian Wang, Min Zheng, Rong Jiang, Shifang Luo
Rok vydání:	2015
Předmět:	Male medicine.medical_specialty Neurite Hyperphosphorylation Mice Transgenic Nerve Tissue Proteins tau Proteins CREB Amyloid beta-Protein Precursor Glycogen Synthase Kinase 3 Mice Alzheimer Disease GSK-3 Physiology (medical) Internal medicine Neurites Presenilin-1 medicine Amyloid precursor protein Animals Humans Pharmacology (medical) Senile plaques Enzyme Inhibitors Gap-43 protein GSK3B Cells Cultured Neurons Pharmacology Memory Disorders Glycogen Synthase Kinase 3 beta biology Valproic Acid Brain Original Articles Up-Regulation Psychiatry and Mental health Endocrinology Synapses biology.protein lipids (amino acids peptides and proteins) Signal Transduction
Zdroj:	CNS Neuroscience & Therapeutics. 21:887-897
ISSN:	1755-5930
Popis:	Summary 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.
Databáze:	OpenAIRE
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