Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China.
School of Medicine and Centre for Molecular and Medical Research, Deakin University, Waurn Ponds, Victoria, Australia.
Neurobiol Aging. 2019 Jun;78:18-28. doi: 10.1016/j.neurobiolaging.2019.02.003. Epub 2019 Feb 13.
Alzheimer's disease (AD) is the most common type of senile dementia. The antiaging 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 a mouse model of AD. The upregulation of cerebral Klotho expression was mediated by an intracerebroventricular injection of a lentiviral vector that encoded Klotho (LV-KL) in 7-month-old amyloid precursor protein/presenilin 1 transgenic mice. Three months later, LV-KL significantly induced Klotho overexpression in the brain and effectively ameliorated cognitive deficit and AD-like pathology in amyloid precursor protein/presenilin 1 mice. LV-KL induced autophagy activation and protein kinase B/mammalian target of rapamycin inhibition both in AD mice and BV2 murine microglia. These results suggest that the upregulation of Klotho expression in the brain may promote the autophagic clearance of amyloid beta and protect against cognitive deficits in AD mice. These findings highlight the preventive and therapeutic potential of Klotho for the treatment of AD.
阿尔茨海默病（AD）是最常见的老年痴呆症类型。有报道称，抗衰老基因 Klotho 在 AD 患者和动物的大脑中会下降。然而，Klotho 在 AD 进展中的作用仍不清楚。本研究探讨了 Klotho 在 AD 小鼠模型中的作用及其潜在机制。通过向 7 月龄淀粉样前体蛋白/早老素 1 转基因小鼠脑室内注射编码 Klotho 的慢病毒载体（LV-KL）上调脑内 Klotho 表达。3 个月后，LV-KL 可显著诱导脑内 Klotho 过表达，并有效改善淀粉样前体蛋白/早老素 1 小鼠的认知缺陷和 AD 样病理。LV-KL 在 AD 小鼠和 BV2 小鼠小胶质细胞中均可诱导自噬激活和蛋白激酶 B/雷帕霉素靶蛋白抑制。这些结果表明，脑内 Klotho 表达的上调可能促进淀粉样β的自噬清除，并防止 AD 小鼠的认知缺陷。这些发现强调了 Klotho 治疗 AD 的预防和治疗潜力。
