阿尔茨海默病重要分泌酶BACE1及其抑制剂

Alzheimer＇s disease＇s most important secretase BACE1 and its inhibitors

阿尔茨海默病（AD）是一种最为普遍的痴呆。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。因此，通过抑制此两种酶很有可能能够减少Aβ的产生从而延缓病程。由于γ分泌酶有众多重要的生理功能，被抑制后会产生很多较为严重的副作用，因此β分泌酶的抑制剂可能是对抗AD药物研发的更有效切入点。本文主要对影响BACE1的表达及活性的相关因素和最新研制成功的β分泌酶抑制剂做简要综述。

Alzheimer＇s disease（AD）, the most common dementia especially in the west, is characterized by the progressive formation of insoluble extracellular amyloid plaques（Aβ） and intracellular fibrillary tangles which are formed by hyperphosphorylated tau. The extracellular aggregations are mainly composed by Aβ42, which is produced by sequential proteolytic processing of β--amyloid precursor pro tein（APP） by two enzymes, β--secretase and γ--secretase. Therefore, the inhibition of these two enzymes could probably reduce the production of Aβ and in turn delay or halt the progression of AD. Since the γ-secretase has too many important functions, inhibiting of which could give rise to serious side effects, β--secretase inhibitors could be a promising way to attenuate the AD pathology. In this paper, we review the regulating factors of BACE1 and some of the most recent BACE1 inhibitors.