胰岛素
胰岛素受体
内分泌学
内科学
医学
血脑屏障
发病机制
下调和上调
胰岛素样生长因子
β淀粉样蛋白
脑脊液
生长因子
胰岛素抵抗
受体
生物
疾病
中枢神经系统
基因
生物化学
作者
Johanna Zemva,Markus Schubert
出处
期刊:Cns & Neurological Disorders-drug Targets
[Bentham Science]
日期:2014-04-01
卷期号:13 (2): 322-337
被引量:52
标识
DOI:10.2174/18715273113126660141
摘要
Recent data suggest that brains of patients with Alzheimer's disease (AD) are insulin and insulin-like growth factor-1 (IGF-1) resistant. So far, there have been two different approaches to investigate possible therapeutic implications of modulating cerebral insulin/IGF-1 signaling (IIS) in AD. One approach is peripheral or intranasal administration of insulin or IGF-1. Intranasal and peripheral insulin administration has been shown to improve memory in patients with AD. Additionally, peripheral IGF-1 administration resulted in decreased amyloid-beta (Aβ) levels in brains of AD mouse models accompanied by elevated Aβ levels in the cerebrospinal fluid (CSF). Insulin and IGF-1 regulate multicargotransporters influencing trafficking of several molecules including Aβ from the brain to the blood as well as to the CSF and possibly vice versa. Furthermore, insulin and related peptides regulate neurovascular coupling changing regional blood flow. Thus, positive effects of peripheral insulin/IGF-1 administration on AD pathology might be due to changes in the blood-brain-barrier (BBB) and/or in the transport between the CSF/blood and the brain. Clinical and experimental data suggest that increased serum insulin and IGF-1 levels do not necessarily correlate with an upregulation of neuronal insulin/IGF-1 receptor signaling. Therefore, the second approach in investigating the role of neuronal IIS for the pathogenesis of AD analyzes knockout mice lacking components of the IIS in AD models. Haploinsufficiency of the IGF- 1 receptor (IGF-1R) (IGF-1R+/- mice) as well as neuronal deficiency of the insulin receptor (IR) (nIR-/- mice) or IGF-1R (nIGF-1R-/- mice) leads to delayed Aβ accumulation when crossed with mouse models for AD. Furthermore, insulin receptor substrate (IRS)-2 knockout mice (IRS-2-/- mice) show reduced Aβ levels in an Alzheimer background. These data suggest beneficial effects of decreased neuronal IIS on Alzheimer-pathology and question the therapeutic outcome of long-term administration of insulin or IGF-1 in patients with AD. Whether the observed phenomenon of cerebral insulin and IGF-1 resistance even at an early stage of Alzheimer's disease is cause, consequence or possibly counter-regulation to AD-pathology needs further investigation and should lead to critical discussions. The current review discusses the pros and cons of targeting insulin/IGF-1 signaling as therapeutic approach for AD. Keywords: Amyloid, Alzheimer's disease, diabetes mellitus, insulin-like growth factor-1 receptor, insulin receptor, insulin receptor substrates, tau.
科研通智能强力驱动
Strongly Powered by AbleSci AI