OBJECTIVE Alzheimer disease(AD) is the most common type of senile dementia. The anti-aging gene Klotho is reported to decline in the brain of patients and animals with AD. However, the role of Klotho in the progressio...OBJECTIVE Alzheimer disease(AD) is the most common type of senile dementia. The anti-aging gene Klotho is reported to decline in the brain of patients and animals with AD. However, the role of Klotho in the progression of AD remains elusive. The present study explored the effects and underlying mechanism of Klotho in amyloid precursor protein/presenilin 1(APP/PS1) transgenic mice. METHODS The upregulation of cerebral Klotho expression was mediated by intracerebroventricular administration of a lentiviral vector that encoded Klotho(LV-KL) in APP/PS1 transgenicmice.RESULTS LV-KL significantly increased Klotho overexpression and effectively ameliorated cognitive deficits and AD-like pathology in aged AD mice. LV-KL might induce autophagy activation and protein kinase B/mammalian target of rapamycin inhibition in both AD mice and cultured BV2 murine microglia. Meanwhile, LV-KL altered the expression of low density lipoprotein receptor-related protein 1(LRP-1), receptor for advanced glycation end products, P-glycoprotein and ABCA1 both at the brain microvascular and choroid plexus as well as the contents of plasma s LRP-1 in aged AD mice.CONCLUSION The current results indicate that Klotho plays a crucial role in the clearance of cerebral amyloid β protein and the progression of AD in mice. These findings highlight the preventive and therapeutic potential of Klotho for the treatment of AD.展开更多
目的研究二价金属离子转运体1(divalent metal transporter 1,DMT1)在APP/PS1转基因小鼠大脑皮层内的定位分布,探讨DMT1异常表达影响脑铁代谢平衡从而参与AD发病的可能机制。方法应用免疫组织化学方法观察DMT1在9月龄APPsw/PS1小鼠大脑...目的研究二价金属离子转运体1(divalent metal transporter 1,DMT1)在APP/PS1转基因小鼠大脑皮层内的定位分布,探讨DMT1异常表达影响脑铁代谢平衡从而参与AD发病的可能机制。方法应用免疫组织化学方法观察DMT1在9月龄APPsw/PS1小鼠大脑皮层的阳性分布;应用免疫荧光双标技术和共聚焦激光扫描显微镜观察DMT1蛋白和β淀粉样蛋白(β-amyloid peptide,Aβ)在APP/PS1转基因小鼠大脑皮层老年斑内的一致性分布和位置关系。结果APP/PS1转基因小鼠大脑皮层老年斑内均有DMT1阳性表达;DMT1和Aβ免疫双标发现DMT1免疫阳性产物与Aβ共存于老年斑,二者分布具有一致性。结论DMT1在APP/PS1转基因小鼠大脑皮层老年斑内大量表达,其分布与Aβ具有一致性,提示DMT1可能参与AD脑内Aβ沉积和老年斑形成。展开更多
文摘OBJECTIVE Alzheimer disease(AD) is the most common type of senile dementia. The anti-aging gene Klotho is reported to decline in the brain of patients and animals with AD. However, the role of Klotho in the progression of AD remains elusive. The present study explored the effects and underlying mechanism of Klotho in amyloid precursor protein/presenilin 1(APP/PS1) transgenic mice. METHODS The upregulation of cerebral Klotho expression was mediated by intracerebroventricular administration of a lentiviral vector that encoded Klotho(LV-KL) in APP/PS1 transgenicmice.RESULTS LV-KL significantly increased Klotho overexpression and effectively ameliorated cognitive deficits and AD-like pathology in aged AD mice. LV-KL might induce autophagy activation and protein kinase B/mammalian target of rapamycin inhibition in both AD mice and cultured BV2 murine microglia. Meanwhile, LV-KL altered the expression of low density lipoprotein receptor-related protein 1(LRP-1), receptor for advanced glycation end products, P-glycoprotein and ABCA1 both at the brain microvascular and choroid plexus as well as the contents of plasma s LRP-1 in aged AD mice.CONCLUSION The current results indicate that Klotho plays a crucial role in the clearance of cerebral amyloid β protein and the progression of AD in mice. These findings highlight the preventive and therapeutic potential of Klotho for the treatment of AD.
文摘目的研究二价金属离子转运体1(divalent metal transporter 1,DMT1)在APP/PS1转基因小鼠大脑皮层内的定位分布,探讨DMT1异常表达影响脑铁代谢平衡从而参与AD发病的可能机制。方法应用免疫组织化学方法观察DMT1在9月龄APPsw/PS1小鼠大脑皮层的阳性分布;应用免疫荧光双标技术和共聚焦激光扫描显微镜观察DMT1蛋白和β淀粉样蛋白(β-amyloid peptide,Aβ)在APP/PS1转基因小鼠大脑皮层老年斑内的一致性分布和位置关系。结果APP/PS1转基因小鼠大脑皮层老年斑内均有DMT1阳性表达;DMT1和Aβ免疫双标发现DMT1免疫阳性产物与Aβ共存于老年斑,二者分布具有一致性。结论DMT1在APP/PS1转基因小鼠大脑皮层老年斑内大量表达,其分布与Aβ具有一致性,提示DMT1可能参与AD脑内Aβ沉积和老年斑形成。
