title: Long-term treatment with intranasal insulin ameliorates cognitive impairment, tau hyperphosphorylation, and microglial activation in a streptozotocin-induced Alzheimer's rat model.
abstract: Recent evidence reveals that aberrant brain insulin signaling plays an important role in the pathology of Alzheimer's disease (AD). Intranasal insulin administration has been reported to improve memory and attention in healthy participants and in AD patients. However, the underlying molecular mechanisms are poorly understood. Here, we treated intracerebroventricular streptozotocin-injected (ICV-STZ) rats, a commonly used animal model of sporadic AD, with daily intranasal delivery of insulin (2 U/day) for 6 consecutive weeks and then studied their cognitive function with the Morris water maze test and biochemical changes via Western blotting. We observed cognitive deficits, tau hyperphosphorylation, and neuroinflammation in the brains of ICV-STZ rats. Intranasal insulin treatment for 6 weeks significantly improved cognitive function, attenuated the level of tau hyperphosphorylation, ameliorated microglial activation, and enhanced neurogenesis in ICV-STZ rats. Additionally, our results indicate that intranasal delivery of insulin probably attenuates tau hyperphosphorylation through the down-regulation of ERK1/2 and CaMKII in the brains of ICV-STZ rats. Our findings demonstrate a beneficial effect of intranasal insulin and provide the mechanistic basis for treating AD patients with intranasal insulin.
authors.affiliation: Department of Neurology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China.
authors.forename: Zhangyu
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Neurology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China.
authors.forename: Yanxing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Neurology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China.
authors.forename: Yan-Fang
authors.initials: YF
authors.lastname: Mao
authors.affiliation: Department of Neurology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Zheng
authors.affiliation: Department of Neurology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China.
authors.forename: Yasi
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Neurology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Neurology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China.
authors.forename: Xinzhen
authors.initials: X
authors.lastname: Yin
authors.affiliation: Department of Neurology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China.
authors.forename: Baorong
authors.initials: B
authors.lastname: Zhang
mesh_terms: D000281:Administration, Intranasal; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D015536:Down-Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D007328:Insulin / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D000089622:Doublecortin Domain Proteins; D007328:Insulin; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D016875:tau Proteins; D013311:Streptozocin; D038362:Glycogen Synthase Kinase 3; C080888:tau-protein kinase; D010749:Phosphoprotein Phosphatases