Development of apomorphine therapy for Alzheimer disease

阿尔茨海默病（Alzheimer's disease，AD）是老年人中最常见的痴呆。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疾病的新型药物。阿扑吗啡（apomorphine，APO）是一种靶向β淀粉样蛋白42（amyloid-β42，Aβ42）在神经元早期聚集的新型药物。本课题利用培养细胞、AD小鼠模型（3xTg-AD）和AD患者脑组织，证实了1）聚集在神经元内的Aβ42主要是毒性转角形成的Aβ42寡聚体，2）毒性转角Aβ 42寡聚体的聚集与内质网应激有关，3）Aβ42寡聚体的聚集与内质网应激有关，4）Aβ42寡聚体的聚集与内质网应激有关。3）APO处理促进毒性turn Aβ42寡聚体的降解：4）APO处理对AD小鼠模型的作用比锂处理更有效，抑制tau蛋白的过度磷酸化; 5）Apokyn（R），一种用于帕金森病患者的APO药物，在低剂量下对AD小鼠模型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能提高培养细胞中胰岛素降解酶（IDE）的活性; APO的作用机制之一可能是通过抑制胰岛素抵抗而提高IDE活性。本研究拟探讨AD小鼠模型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。

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.