Valproic Acid Modifies Synaptic Structure and Accelerates Neurite Outgrowth Via the Glycogen Synthase Kinase-3ß Signaling Pathway in an Alzheimer's Disease Model.
CNS Neurosci Ther
; 21(11): 887-97, 2015 Nov.
Article
en En
| MEDLINE
| ID: mdl-26385876
ABSTRACT
AIM:
Tau hyperphosphorylation and amyloid ß-peptide overproduction, caused by altered localization or abnormal activation of glycogen synthase kinase-3ß (GSK-3ß), 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-3ß (pSer9-GSK-3ß) 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-3ß, decreasing hyperphosphorylated tau, enhancing CREB and BDNF expression.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Sinapsis
/
Transducción de Señal
/
Ácido Valproico
/
Neuritas
/
Glucógeno Sintasa Quinasa 3
/
Inhibidores Enzimáticos
/
Enfermedad de Alzheimer
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
CNS Neurosci Ther
Asunto de la revista:
NEUROLOGIA
/
TERAPEUTICA
Año:
2015
Tipo del documento:
Article
País de afiliación:
China