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Development of apomorphine therapy for Alzheimer disease

阿朴吗啡治疗阿尔茨海默病的进展

基本信息

批准号：
22590936
负责人：
OHYAGI Yasumasa
金额：
$ 2.91万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2012
项目状态：
已结题

项目摘要

Alzheimer’s disease (AD) is the most frequent dementia in the elderly. However, the currently approved drugs’ effects on cognitive function are only slight, and novel drugs that improve memory function and inhibit neurodegeneration are being developed. We have found apomorphine (APO) to be a novel drug that targets amyloid-β42 (Aβ42) accumulating early in the neurons. In the present research theme, using cultured cells, AD mouse model (3xTg-AD) and brain tissues of AD patients, we have demonstrated1) that the majority of Aβ42 accumulating in the neurons is the Aβ42 oligomer with toxic turn formation;2) that accumulation of the toxic turn Aβ42 oligomer is associated wuth endoplasmic reticulum stress;3) that APO treatment promotes degradation of the toxic turn Aβ42 oligomer;4) APO treatment is more effective for the AD mouse model than lithium treatment which inhibits hyper-phosphrylation of tau protein;5) that Apokyn（R）, a drug of APO for Parkinson’s disease patients, is effective enough at low dose for memory function of the AD mouse model;6) that the anti-AD effects of APO is not simply due to stimulation of dopamine receptors;7) that APO elevates the activity of Insulin-degrading enzyme (IDE) in the cultured cells; and8) that one of the molecular mechanisms of APO effects may be inhibition of the insulin resistance leading to elevation of the IDE activity.In the future, we will study about elevation of the insulin resistance in the brains of the AD mouse model and effects of APO treatment on the insulin resistance, and develop new drugs for the brain diabetes in AD.

阿尔茨海默病(AD)是老年人最常见的痴呆症。然而，目前批准的药物对认知功能的影响很小，正在开发改善记忆功能和抑制神经退行性变的新药。我们发现阿朴吗啡是一种针对淀粉样蛋白42(Aβ42，Aβ42)的新药，它在神经元中早期积聚。在本研究中，利用培养细胞、AD小鼠模型(3xTg-AD)和AD患者的脑组织，我们已经证明：1)在神经元中积聚的大部分Aβ42是形成毒性TURN的Aβ42寡聚体；2)毒性TURN Aβ42寡聚体的积累与内质网应激有关；3)APO处理促进了有毒TURE Aβ42寡聚体的降解；4)APO治疗AD小鼠模型比锂治疗更有效，后者抑制tau蛋白的过度磷酸化；5)治疗帕金森病患者的APO药物Apokyn(R)在低剂量下对AD模型小鼠的记忆功能足够有效；6)APO的抗AD作用不仅仅是由于刺激多巴胺受体；7)APO提高培养细胞中胰岛素降解酶(IDE)的活性；8)APO作用的分子机制之一可能是抑制胰岛素抵抗导致的IDE活性升高。今后，我们将研究AD模型小鼠脑内胰岛素抵抗的升高及APO治疗对胰岛素抵抗的影响，并开发治疗AD脑糖尿病的新药。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intracellular accumulation of toxic turn amyloid-β associated with endoplasmic reticulum stress in Alzheimer'sdisease.

细胞内有毒转淀粉样蛋白-β的积累与阿尔茨海默病的内质网应激相关。

DOI：
发表时间：
2012
期刊：
影响因子：
0
作者：
Kitamura;Y.;Doi;M.;Kuwatsuka;K.;Onoue;Y.;Miyazaki;I.;Shinomiya;K.;Koyama;T.;Sendo;T.;Kawasaki;H.;Asanuma;M. and Gomita;Y.;Ohyagi Y et al
通讯作者：
Ohyagi Y et al

Aluminium and Alzheimer's disease: An update

铝和阿尔茨海默病：最新进展