title: Activation of sirtuin 1 attenuates cerebral ventricular streptozotocin-induced tau hyperphosphorylation and cognitive injuries in rat hippocampi.
abstract: Patients with diabetes in the aging population are at high risk of Alzheimer's disease (AD), and reduction of sirtuin 1 (SIRT1) activity occurs simultaneously with the accumulation of hyperphosphorylated tau in the AD-affected brain. It is not clear, however, whether SIRT1 is a suitable molecular target for the treatment of AD. Here, we employed a rat model of brain insulin resistance with intracerebroventricular injection of streptozotocin (ICV-STZ; 3 mg/kg, twice with an interval of 48 h). The ICV-STZ-treated rats were administrated with resveratrol (RSV; SIRT1-specific activator) or a vehicle via intraperitoneal injection for 8 weeks (30 mg/kg, once per day). In ICV-STZ-treated rats, the levels of phosphorylated tau and phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2) at the hippocampi were increased significantly, whereas SIRT1 activity was decreased without change of its expression level. The capacity of spatial memory was also significantly lower in ICV-STZ-treated rats compared with age-matched control. RSV, a specific activator of SIRT1, which reversed the ICV-STZ-induced decrease in SIRT1 activity, increases in ERK1/2 phosphorylation, tau phosphorylation, and impairment of cognitive capability in rats. In conclusion, SIRT1 protects hippocampus neurons from tau hyperphosphorylation and prevents cognitive impairment induced by ICV-STZ brain insulin resistance with decreased hippocampus ERK1/2 activity.
authors.affiliation: Department of Pathophysiology, Key Laboratory of Neurological Diseases of Education Ministry of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Lai-Ling
authors.initials: LL
authors.lastname: Du
authors.forename: Jia-Zhao
authors.initials: JZ
authors.lastname: Xie
authors.forename: Xiang-Shu
authors.initials: XS
authors.lastname: Cheng
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Li
authors.forename: Fan-Li
authors.initials: FL
authors.lastname: Kong
authors.forename: Xia
authors.initials: X
authors.lastname: Jiang
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Ma
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Xin-Wen
authors.initials: XW
authors.lastname: Zhou
mesh_terms: D000375:Aging; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D015153:Blotting, Western; D002552:Cerebral Ventricles / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D005470:Fluorometry; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000096:biosynthesis* / Q000187:drug effects; D013267:Stilbenes / Q000008:administration & dosage*; D013311:Streptozocin / Q000633:toxicity; D014665:Vasodilator Agents; D016875:tau Proteins / Q000187:drug effects / Q000378:metabolism
chemical_list: D000975:Antioxidants; D013267:Stilbenes; D014665:Vasodilator Agents; D016875:tau Proteins; D013311:Streptozocin; D056564:Sirtuin 1; D000077185:Resveratrol