Amyloid 13-peptide, a major component of senile plaques in Alzheimer＇s disease, has been implicated in neuronal cell death and cognitive impairment. Recently, studies have shown that the pathogenesis of cerebral isch...Amyloid 13-peptide, a major component of senile plaques in Alzheimer＇s disease, has been implicated in neuronal cell death and cognitive impairment. Recently, studies have shown that the pathogenesis of cerebral ischemia is closely linked with Alzheimer＇s disease. In this study, a rat model of global cerebral ischemia-reperfusion injury was established via occlusion of four arteries; meanwhile, fibrillar amyloid [3-peptide was injected into the rat lateral ventricle. The Morris water maze test and histological staining revealed that administration of amyloid 13-peptide could further aggravate impairments to learning and memory and neuronal cell death in the hippocampus of rats subjected to cerebral ischemia-reperfusion injury. Western blot showed that phosphorylation of tau protein and the activity of glycogen synthase kinase 313 were significantly stronger in cerebral ischemia-reperfusion injury rats subjected to amyloid [3-peptide administration than those undergo- ing cerebral ischemia-repetfusion or amyloid 13-peptide administration alone. Conversely, the activ- ity of protein phosphatase 2A was remarkably reduced in rats with cerebral ischemia-reperfusion injury following amyloid 13-peptide administration. These findings suggest that amyloid 13-peptide can potentiate tau phosphorylation induced by cerebral ischemia-reperfusion and thereby aggravate cognitive impairment.展开更多
Decreased expression of brain-derived neurotrophic factor（BDNF） plays an important role in the pathogenesis of Alzheimer＇s disease, and a typical pathological change in Alzheimer＇s disease is neurofibrillary tangl...Decreased expression of brain-derived neurotrophic factor（BDNF） plays an important role in the pathogenesis of Alzheimer＇s disease, and a typical pathological change in Alzheimer＇s disease is neurofibrillary tangles caused by hyperphosphorylation of tau. An in vivo model of Alzheimer＇s disease was developed by injecting okadaic acid（2 μL） and exogenous BDNF（2 μL） into the hippocampi of adult male Wister rats. Spatial learning and memory abilities were assessed using the Morris water maze. The expression levels of protein phosphatase 2 A（PP2 A）, PP2 Ac-Yp307, p-tau（Thr231）, and p-tau（Ser396/404） were detected by western blot assay. The expression levels of BDNF, TrkB, and synaptophysin mRNA were measured by quantitative real-time polymerase chain reaction. Our results indicated that BDNF expression was suppressed in the hippocampus of OA-treated rats, which resulted in learning and memory deficits. Intra-hippocampal injection of BDNF attenuated this OA-induced cognitive impairment. Finally, our findings indicated an involvement of the PI3 K/GSK-3β/AKT pathway in the mechanism of BDNF in regulating cognitive function. These results indicate that BDNF has beneficial effect on Alzheimer＇s disease, and highlight the potential of BDNF as a drug target for treatment of Alzheimer＇s disease.展开更多
基金supported by the National High Technology Research and Development Program of China("863"Program),No.2012AA020905the National Natural Science Foundation of China,No.81171143 and30971011+1 种基金National Natural Science Foundation of China(NSFC)/Research Grants Council(RGC) Joint Research Scheme,No.81161160570TsinghuaYue-Yuen Medical Sciences Fund
文摘Amyloid 13-peptide, a major component of senile plaques in Alzheimer＇s disease, has been implicated in neuronal cell death and cognitive impairment. Recently, studies have shown that the pathogenesis of cerebral ischemia is closely linked with Alzheimer＇s disease. In this study, a rat model of global cerebral ischemia-reperfusion injury was established via occlusion of four arteries; meanwhile, fibrillar amyloid [3-peptide was injected into the rat lateral ventricle. The Morris water maze test and histological staining revealed that administration of amyloid 13-peptide could further aggravate impairments to learning and memory and neuronal cell death in the hippocampus of rats subjected to cerebral ischemia-reperfusion injury. Western blot showed that phosphorylation of tau protein and the activity of glycogen synthase kinase 313 were significantly stronger in cerebral ischemia-reperfusion injury rats subjected to amyloid [3-peptide administration than those undergo- ing cerebral ischemia-repetfusion or amyloid 13-peptide administration alone. Conversely, the activ- ity of protein phosphatase 2A was remarkably reduced in rats with cerebral ischemia-reperfusion injury following amyloid 13-peptide administration. These findings suggest that amyloid 13-peptide can potentiate tau phosphorylation induced by cerebral ischemia-reperfusion and thereby aggravate cognitive impairment.
文摘Decreased expression of brain-derived neurotrophic factor（BDNF） plays an important role in the pathogenesis of Alzheimer＇s disease, and a typical pathological change in Alzheimer＇s disease is neurofibrillary tangles caused by hyperphosphorylation of tau. An in vivo model of Alzheimer＇s disease was developed by injecting okadaic acid（2 μL） and exogenous BDNF（2 μL） into the hippocampi of adult male Wister rats. Spatial learning and memory abilities were assessed using the Morris water maze. The expression levels of protein phosphatase 2 A（PP2 A）, PP2 Ac-Yp307, p-tau（Thr231）, and p-tau（Ser396/404） were detected by western blot assay. The expression levels of BDNF, TrkB, and synaptophysin mRNA were measured by quantitative real-time polymerase chain reaction. Our results indicated that BDNF expression was suppressed in the hippocampus of OA-treated rats, which resulted in learning and memory deficits. Intra-hippocampal injection of BDNF attenuated this OA-induced cognitive impairment. Finally, our findings indicated an involvement of the PI3 K/GSK-3β/AKT pathway in the mechanism of BDNF in regulating cognitive function. These results indicate that BDNF has beneficial effect on Alzheimer＇s disease, and highlight the potential of BDNF as a drug target for treatment of Alzheimer＇s disease.
