Taxifolin Prevents β-amyloid-induced Impairments Of Synaptic Formation And Deficits Of Memory Via The Inhibition Of Cytosolic Phospholipase A2/Prostaglandin E2 Content

Objective: Alzheimer’s disease(AD)is a progressive neurodegenerative disease characterized with cognitive deficits and memory impairments.β-amyloid(Aβ)is one of the main pathogenic factors of AD.The abnormal accumulation of Aβ can lead to synaptic damaged and neurotoxicity.So far,there still have no effective drugs for the therapy of AD.Taxifolin(TAX)is a flavonoid extracted from natural plants.It has been reported to have the effect of anti-inflammatory,anti-oxidation and scavenging free radicals.Studies have shown that TAX can reduce oligomer Aβ accumulation,but the main mechanism of TAX in Aβ-oligomers-mediated cognitive impairment is unclear.In this study,molecular techniques,live-cell imaging techniques and behavioral methods were used to investigate the role and the underlying mechanisms of TAX in soluble Aβ-oligomersmediated synaptogenesis and cognitive impairments.Methods:(1)MTT assay was used to detect the cell viability of TAX and / or Aβ42 oligomers treated SH-SY5 Y cells,and to find out the role of TAX and whether it can prevent neuronal cells death induced by oligmeric Aβ42.(2)Primary cultured neurons were co-transfected with GFP-actin and F-GFP on day 5 in vitro(DIV 5)to show the morphological structure of hippocampal neurons.The number and length of dendritic filopodia were detected using cofocal imaging to analyze the effect of soluble Aβ42-oligmers on dendritic at DIV 7,and to investigate whether TAX can prevent the damage of dendritic filopodia induced by Aβ42-oligmers.At DIV 14,the effect of soluble Aβ42 and TAX on dendritic spine density was examined using live-cell imaging to detect whether TAX can inhibit Aβ42-induced injury of dendritic spines.(3)The novel object recognition experiments and morris water maze tests were used to detect the recognition and spatial memory of AD model mice,and to analyze whether TAX can improve the impairment of learning and memory function of mice induced by Aβ42-oligmers.(4)Western blotting(WB)technique was used to detect the expression of postsynaptic density protein 95(PSD 95)in the hippocampus of the experimental mice.The effects of different doses of TAX on hippocampal synaptic damage induced by Aβ42-oligmers in mice were analyzed.(5)Enzyme linked immunosorbent assay(ELISA)was used to detect the content of Prostaglandin E2(PGE2)and Cytosolic phospholipase A2(cPLA2)in cultured hippocampal neurons and hippocampal tissues of experimental mice,to find out whether TAX can inhibit the increased content of PGE2 and cPLA2 caused by soluble oligomer Aβ42.Results:(1)TAX prevented SH-SY5 Y cell death induced by oligomeric Aβ42 in a dosedependent manner.(2)TAX prevented dendritic filopodia injuried by oligomeric Aβ42 in hippocampal neurons.(3)TAX prevented synaptic damage caused by oligomeric Aβ42 in hippocampal neurons.(4)TAX improved cognitive deficits and spatial memory impairments in mice induced by oligomer Aβ42.(5)Taxifolin prevented the decrease of PSD 95 in hippocampus induced by Aβ42 in mice.(6)TAX prevented oligomeric Aβ42-induced elevation of cPLA2 and PGE2 levels in hippocampal neurons and tissues.Conclusion: TAX prevent the damage of dendritic filopodia and synaptic induced by soluble oligomer Aβ42,and improve AD cognitive dysfunction.The prevention effect of TAX on synaptic and cognitive impairment induced by oligomeric Aβ42 may through decreasing the content of cPLA2 and PGE2.This study provides new insights into the mechanism of TAX on protects against AD.