Lentivirus-mediated klotho up-regulation improves aging-related memory deficits and oxidative stress in senescence-accelerated mouse prone-8 mice

LIFE SCIENCES

卷:200

Article

Zhou, Hong-Jing¹  Zeng, Chen-Ye¹  Yang, Ting-Ting¹  Long, Fang-Yi¹  Kuang, Xi¹  Du, Jun-Rong¹ 

[1] Sichuan Univ, West China Sch Pharm, Dept Pharmacol, Key Lab Drug Targeting & Drug Delivery Syst, Chengdu 610041, Sichuan, Peoples R China

关键词: Klotho;    Aging;    Lentivirus;    Memory deficits;    Oxidative stress;    FoxO1 signaling;   

DOI  :  10.1016/j.lfs.2018.03.027

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

Free