人β-分泌酶与阿尔茨海默病

Human beta-secretase and Alzheimer's disease

阿尔茨海默病(AD)是最常见的引起痴呆的神经退行性疾病,主要表现为进行性的认知功能障碍和行为能力障碍,其病理特征是神经细胞外不溶性淀粉样蛋白Aβ以及胞内由过磷酸化tau形成的纤维缠结.这种胞外聚合物主要由Aβ4两组成,它是由淀粉样前体蛋白APP依次经β分泌酶(β-secretase)和γ分泌酶(γ-secretase)剪切所产生的。沉积和细胞内过量的Tau蛋白磷酸化形成神经纤维缠结(NFTs),从而引起氧化应激和慢性炎症损伤,导致神经元丢失和突触功能障碍。基于对AD病理特征认识,以往将针对Aβ和NFTs的治疗作为AD治疗的主要方向,但是经过数十年的研究并未取得长足的进展。近年来,随着人们对B淀粉蛋白前体蛋白(APP)处理途径的认识不断深入,人们越来越重视APP降解产生Aβ的关键酶在AD发病中的作用。因此,本文就人β-分泌酶(β-secreatase,BACE1)的相关特性及在AD发病中的相关作用,以及在AD治疗中的研究进展做一综述。

Alzheimer＇s disease （AD） is the most common cause of dementia, neurodegenera-tive diseases, mainly characterized by progressive cognitive dysfunction and behavioral disabilities, its pathological characteristics are nerve cells outside insoluble amyloid beta and intracellular fiber which is formed by a phosphorylated tau tangles. This kind of extracellular oligomeric is mainly composed of Aβ, which is sequentially cleavaged the amyloid precursor protein APP byβ-secretase andγ-secretase. Deposition and excessive tau protein phosphorylation in cells form a nerve fiber tangles （NFTs）, so as to cause oxidative stress and chronic inflammation damage, which leads to neuronal loss and synaptic dysfunction. In the past, based on the understanding of AD pathology characteristics, we focused on Aβand NFTs as the main direction of AD treatment, but over decades of research we have not made great progress. In recent years, as the in-depth and developmental understanding of beta amyloid protein precursor protein （APP） processing, people pay more and more attention toβ-site APP-Cleav-ing Enzyme 1, a key enzyme in Alzheimer disease （AD）. Therefore, theβ-secretase （BACE1） related features ,functions and the related treatment progress in Alzheimer disease are reviewed in this paper.