Lentivirus-mediated klotho up-regulation improves aging-related memory deficits and oxidative stress in senescence-accelerated mouse prone-8 mice
Lentivirus-mediated klotho up-regulation improves aging-related memory deficits and oxidative stress in senescence-accelerated mouse prone-8 mice
复制标题
慢病毒介导的klotho上调可改善衰老加速小鼠pron-8小鼠中与衰老相关的记忆缺陷和氧化应激
DOI：
10.1016/j.lfs.2018.03.027
复制
发表时间：
2018-05-01
期刊：
影响因子：
6.1
通讯作者：
Du, Jun-Rong
中科院分区：
文献类型：
--
作者：
Zhou, Hong-Jing;Zeng, Chen-Ye;Du, Jun-Rong
目的：衰老引起的氧化应激会加剧神经病理变化和认知缺陷。 Klotho 是一种抗衰老蛋白，具有抗氧化作用。本研究的目的是确定 klotho 对衰老加速小鼠 pron-8 (SAMP8) 小鼠衰老相关神经病理变化和记忆障碍的潜在治疗作用，并确定这些神经保护作用的潜在机制。 材料和方法：使用慢病毒传递和维持 klotho 的表达。将慢病毒载体注射到7个月大的SAMP8小鼠或年龄匹配的SAMR1小鼠的双侧侧脑室中。三个月后，采用Y迷宫交替任务和被动回避任务来评估小鼠的记忆缺陷。随后的研究中应用了原位杂交、免疫组化、免疫荧光、尼氏染色、实时定量PCR和Western blot检测。主要发现：我们的结果显示，注射编码全长klotho基因的慢病毒载体后3个月，10月龄的SAMP8小鼠脑中klotho的表达显着增加。这种治疗减少了记忆缺陷、神经元损失、突触损伤和 4-HNE 水平，但增加了线粒体锰超氧化物歧化酶 (Mn-SOD) 和过氧化氢酶 (CAT) 的表达。此外，klotho 表达的上调降低了 Akt 和 Forkhead box O1 (FoxO1) 磷酸化。
Aims: Oxidative stress caused by aging aggravates neuropathological changes and cognitive deficits. Klotho, an anti-aging protein, shows an anti-oxidative effect. The aims of the present study were to determine the potential therapeutic effect of klotho in aging-related neuropathological changes and memory impairments in senescence-accelerated mouse prone-8 (SAMP8) mice, and identify the potential mechanism of these neuroprotective effects.Materials and methods: A lentivirus was used to deliver and sustain the expression of klotho. The lentiviral vectors were injected into the bilateral lateral ventricles of 7-month-old SAMP8 mice or age-matched SAMR1 mice. Three months later, the Y-maze alternation task and passive avoidance task were used to assess the memory deficits of the mice. In situ hybridization, immunohistochemistry, immunofluorescence, Nissl staining, quantitative real-time PCR and Western blot assays were applied in the following research.Key findings: Our results showed that 3 months after injection of the lentiviral vectors encoding the full-length klotho gene, the expression of klotho in the brain was significantly increased in 10-month-old SAMP8 mice. This treatment reduced memory deficits, neuronal loss, synaptic damage and 4-HNE levels but increased mitochondrial manganese-superoxide dismutase (Mn-SOD) and catalase (CAT) expression. Moreover, the up-regulation of klotho expression decreased Akt and Forkhead box class O1 (FoxO1) phosphorylation.