Molecular mechanism of apomorphine therapy for Alzheimer disease

阿尔茨海默病（AD）是老年痴呆症的主要病因，治疗药物的开发是一个重要问题。我们发现阿波啡（apopine， APO）是一种靶向淀粉样蛋白-β42 （a -β42）在神经元中早期积累的新型药物。在本研究中，我们揭示了1)APO的抗ad作用不仅仅是由于刺激多巴胺受体；2) APO可提高培养细胞中胰岛素降解酶（IDE）的活性；3) APO作用的分子机制之一可能是抑制胰岛素抵抗和提高IDE活性；4) APO处理对AD小鼠模型（3xTg-AD）比锂处理更有效，锂处理抑制tau蛋白的超磷酸化；5) Apokyn(R)是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。然而，我们研究了细胞内Aβ的性质，并证明在3xTg-AD小鼠记忆功能障碍诱发内质网应激发生之前，毒性转化Aβ42在神经元中积累。

Alzheimer’s disease (AD) is the major cause of senile dementia, and development of curative drugs is an important issue. We have found apomorphine (APO) to be a novel drug that targets amyloid-β42 (Aβ42) accumulating early in the neurons. In the present research, we revealed 1) that the anti-AD effects of APO is not simply due to stimulation of dopamine receptors; 2) that APO elevates the activity of Insulin-degrading enzyme (IDE) in the cultured cells; 3) that one of the molecular mechanisms of APO effects may be inhibition of the insulin resistance and elevation of the IDE activity; 4) that APO treatment is more effective for the AD mouse model (3xTg-AD) than lithium treatment which inhibits hyper-phosphrylation of tau protein; and 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. While, we studied the nature of intracellular Aβ, and have demonstrated that toxic turn Aβ42 accumulates in neurons before onset of memory dysfunction inducing endoplasmic reticulum stress in 3xTg-AD mice.