title: Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APPswe/PS1dE9 mice.
abstract: Brain insulin signaling deficits contribute to multiple pathological features of Alzheimer's disease (AD). Although intranasal insulin has shown efficacy in patients with AD, the underlying mechanisms remain largely unillustrated. Here, we demonstrate that intranasal insulin improves cognitive deficits, ameliorates defective brain insulin signaling, and strongly reduces β-amyloid (Aβ) production and plaque formation after 6 weeks of treatment in 4.5-month-old APPswe/PS1dE9 (APP/PS1) mice. Furthermore, c-Jun N-terminal kinase activation, which plays a pivotal role in insulin resistance and AD pathologies, is significantly inhibited. The alleviation of amyloid pathology by intranasal insulin results mainly from enhanced nonamyloidogenic processing and compromised amyloidogenic processing of amyloid precursor protein (APP), and from a reduction in apolipoprotein E protein which is involved in Aβ metabolism. In addition, intranasal insulin effectively promotes hippocampal neurogenesis in APP/PS1 mice. This study, exploring the mechanisms underlying the beneficial effects of intranasal insulin on Aβ pathologies in vivo for the first time, highlights important preclinical evidence that intranasal insulin is potentially an effective therapeutic method for the prevention and treatment of AD.
authors.affiliation: Department of Neurology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 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, 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, 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, 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, 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, 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, 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, China.
authors.forename: Baorong
authors.initials: B
authors.lastname: Zhang
mesh_terms: D000281:Administration, Intranasal; D000375:Aging / Q000473:pathology*; D000682:Amyloid / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001007:Anxiety / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D003072:Cognition Disorders / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008568:Memory / Q000187:drug effects; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000187:drug effects; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000473:pathology; D053764:Presenilin-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D007328:Insulin; D053764:Presenilin-1; D048031:JNK Mitogen-Activated Protein Kinases
keywords: APP processing; APP/PS1; Alzheimer's disease; amyloid pathology; insulin signaling