title: Autophagy ameliorates cognitive impairment through activation of PVT1 and apoptosis in diabetes mice.
abstract: The underlying mechanisms of cognitive impairment in diabetes remain incompletely characterized. Here we show that the autophagic inhibition by 3-methyladenine (3-MA) aggravates cognitive impairment in streptozotocin-induced diabetic mice, including exacerbation of anxiety-like behaviors and aggravation in spatial learning and memory, especially the spatial reversal memory. Further neuronal function identification confirmed that both long term potentiation (LTP) and depotentiation (DPT) were exacerbated by autophagic inhibition in diabetic mice, which indicating impairment of synaptic plasticity. However, no significant change of pair-pulse facilitation (PPF) was recorded in diabetic mice with autophagic suppression compared with the diabetic mice, which indicated that presynaptic function was not affected by autophagic inhibition in diabetes. Subsequent hippocampal neuronal cell death analysis showed that the apoptotic cell death, but not the regulated necrosis, significantly increased in autophagic suppression of diabetic mice. Finally, molecular mechanism that may lead to cell death was identified. The long non-coding RNA PVT1 (plasmacytoma variant translocation 1) expression was analyzed, and data revealed that PVT1 was decreased significantly by 3-MA in diabetes. These findings show that PVT1-mediated autophagy may protect hippocampal neurons from impairment of synaptic plasticity and apoptosis, and then ameliorates cognitive impairment in diabetes. These intriguing findings will help pave the way for exciting functional studies of autophagy in cognitive impairment and diabetes that may alter the existing paradigms.
authors.affiliation: College of Medicine, State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Animal Models and Degenerative Neurological Diseases, Nankai University, Tianjin 300071, China.
authors.forename: Zhigui
authors.initials: Z
authors.lastname: Li
authors.affiliation: College of Medicine, State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Animal Models and Degenerative Neurological Diseases, Nankai University, Tianjin 300071, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Hao
authors.affiliation: College of Medicine, State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Animal Models and Degenerative Neurological Diseases, Nankai University, Tianjin 300071, China.
authors.forename: Hongqiang
authors.initials: H
authors.lastname: Yin
authors.affiliation: College of Medicine, State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Animal Models and Degenerative Neurological Diseases, Nankai University, Tianjin 300071, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Gao
authors.affiliation: College of Medicine, State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Animal Models and Degenerative Neurological Diseases, Nankai University, Tianjin 300071, China. Electronic address: zhuoyang@nankai.edu.cn.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Yang
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D000071186:Beclin-1 / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003072:Cognition Disorders / Q000209:etiology*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D019580:Perforant Pathway / Q000187:drug effects / Q000502:physiology; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D013311:Streptozocin / Q000633:toxicity
chemical_list: D000903:Antibiotics, Antineoplastic; D000071186:Beclin-1; D007004:Hypoglycemic Agents; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; C000609195:PVT1 long-non-coding RNA, mouse; D062085:RNA, Long Noncoding; C025946:3-methyladenine; D013311:Streptozocin; D000225:Adenine
keywords: Apoptosis; Autophagy; Cognitive impairment; Diabetes; Hippocampus; Long noncoding RNA; PVT1; Regulated necrosis; Synaptic plasticity