阿尔茨海默症病理机制中的金属代谢和金属药物

随着人口老龄化进程的发展,阿尔茨海默症(AD)已成为威胁中国和世界人口健康和经济的重大疾病.本文综述了近年来AD病理的分子机制的新进展,分析了其中金属代谢的意义.研究发现,在AD进程中,围绕淀粉样斑块(AP)和神经缠绕斑(NFT)的形成,多因素相互联系并发挥作用,这些主要因素包括金属内稳态、胰岛素抵抗、神经炎症、线粒体和血脑屏障改变等.与AD病理过程密切相关的主要蛋白质均参与了金属元素的生理代谢过程,而细胞金属离子的内稳态失衡加剧了AD病理的恶化.金属药物在AD诊断和治疗中可能具有以下的发展潜力:(1)AD早期诊断探针;(2)调节金属内稳态的配体和/或微量元素补充;(3)抗糖尿病金属配合物;(4)神经元和血脑屏障(BBB)保护金属药物.

Metallostasis and metal-based drugs for Alzheimer＇s disease

With the advance of aging, Alzheimer＇s disease （AD） is creating unsustainable challenges to healthcare and economy in China and worldwide. Recent researches demonstrated that the mechanism of AD involves a multiple of metabolic disorders, i.e. metallostasis, insulin resistance, neuroinflammation, alteration of mitochondria, and changes of blood brain barrier （BBB） function, linked with each other in the core mechanism of amyloid plaque and neurobrillary tangles （NFT）. Strong evidences indicated that each of the major protein participants in AD pathology has physiologically important interactions with transition metals. The amyloid pathology causes disorders of metal homeostasis in neurons, which inversely aggravate AD progress. Metal-based drugs/agents are of great potential in AD diagnosis and therapy, i.e. （i） probes for early AD diagnosis, （ii） metal ligands and/or complexes modulating metallostasis, （iii） anti-diabetic metal complexes, and （iv） BBB and neuron protective metal compounds.