期刊
AGING CELL
卷 15, 期 5, 页码 893-902出版社
WILEY
DOI: 10.1111/acel.12498
关键词
insulin signaling; amyloid pathology; APP processing; APP; PS1; Alzheimer's disease
资金
- National 973 Project [2013CB530900, 2013CB530904]
- National Nature Science Foundation of China [81400866, 81200984]
- Projects of International Cooperation and Exchanges NSFC [81520108010]
- New Doctorate Teacher Fund from Ministry of Education of China [20120101120036]
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 -amyloid (A) production and plaque formation after 6weeks 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 A 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 A pathologies invivo for the first time, highlights important preclinical evidence that intranasal insulin is potentially an effective therapeutic method for the prevention and treatment of AD.
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