title: Temsirolimus attenuates tauopathy in vitro and in vivo by targeting tau hyperphosphorylation and autophagic clearance.
abstract: In a variety of neurodegenerative tauopathies including Alzheimer's disease, frontotemporal dementia and some types of Parkinson's disease, tau protein is abnormally hyperphosphorylated by several kinases and eventually aggregates to form neurofibrillary tangles, a neurotoxic pathological characteristic that closely correlates with cognitive impairments. Hence, targeting hyperphosphorylated tau protein has now been considered as a valid therapeutic approach for these neurodegenerative tauopathies. As a newly developed analog of rapamycin, temsirolimus was approved by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of renal cell carcinoma. Recent findings suggested that temsirolimus also provided beneficial effects in animal models of Huntington's disease and spinocerebellar ataxia type 3, two neurodegenerative diseases caused by accumulation of aberrant proteins within brain. To date, the therapeutic potentials of temsirolimus in neurodegenerative tauopathies have not been determined. Herein, we demonstrated for the first time that temsirolimus treatment effectively enhanced autophagic clearance of hyperphosphorylated tau in okadaic acid-incubated SH-SY5Y cells and in brain of P301S transgenic mice. Meanwhile, we showed that inactivation of glycogen synthase kinase-3β, the most important tau kinase, might contribute to the temsirolimus-induced reduction of tau hyperphosphorylation in these two tauopathy models. More importantly, temsirolimus administration rescued spatial learning and memory impairments in P301S transgenic mice. These findings highlight temsirolimus administration as a potential therapeutic strategy for neurodegenerative tauopathies.
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, China.
authors.forename: Teng
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, China; Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, China; Department of Neurology, Qingdao Municipal Hospital, College of Medicine and Pharmaceutics, Ocean University of China, China. Electronic address: yu-jintai@163.com.
authors.forename: Jin-Tai
authors.initials: JT
authors.lastname: Yu
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, China.
authors.forename: Xi-Chen
authors.initials: XC
authors.lastname: Zhu
authors.affiliation: Central Laboratory, Nanjing Brain Hospital, Nanjing Medical University, China.
authors.forename: Qiao-Quan
authors.initials: QQ
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, China.
authors.forename: Hui-Fu
authors.initials: HF
authors.lastname: Wang
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, College of Medicine and Pharmaceutics, Ocean University of China, China.
authors.forename: Meng-Shan
authors.initials: MS
authors.lastname: Tan
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Qin
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, China.
authors.forename: Ying-Dong
authors.initials: YD
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, China; Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, China; Department of Neurology, Qingdao Municipal Hospital, College of Medicine and Pharmaceutics, Ocean University of China, China. Electronic address: dr.tanlan@163.com.
authors.forename: Lan
authors.initials: L
authors.lastname: Tan
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019319:Okadaic Acid / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D065853:Spatial Learning / Q000187:drug effects / Q000502:physiology; D065852:Spatial Memory / Q000187:drug effects / Q000502:physiology; D024801:Tauopathies / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; C054369:MAPT protein, human; C558298:Mapt protein, mouse; D018696:Neuroprotective Agents; D016875:tau Proteins; D019319:Okadaic Acid; C401859:temsirolimus; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D020123:Sirolimus
keywords: Autophagy; GSK-3β; Spatial cognitive deficits; Tauopathy; Temsirolimus