β-分泌酶（BACE1）的功能，调控和治疗特性。,Seminars in Cell & Developmental Biology

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β-分泌酶（BACE1）的功能，调控和治疗特性。
Seminars in Cell & Developmental Biology ( IF 6.2 ) Pub Date : 2009-05-12 , DOI: 10.1016/j.semcdb.2009.01.003
Michael Willem ₁ , Sven Lammich , Christian Haass

Affiliation

β-分泌酶（β-位淀粉样蛋白前体蛋白裂解酶1； BACE1）已被确定为淀粉样β-肽（Abeta）生产的限速酶。Abeta是阿尔茨海默氏病（AD）大脑中淀粉样蛋白斑块和血管沉积的主要成分，并被认为会引发致命的淀粉样蛋白级联反应。BACE1是主要的β-分泌酶，因为其敲除完全阻止了Abeta的产生。BACE1可能会处理许多不同的底物，因此BACE1可能会发挥几种独立的生理功能。目前，BACE1在髓鞘形成中的功能已得到最好的了解。BACE1裂解并激活Neuregulin-1，因此在出生后早期发育过程中直接参与周围神经系统的髓鞘形成。然而，迄今为止，对中枢神经系统内其他生理功能的了解还很少。至少在某些AD大脑中BACE1上调。BACE1调控的多种细胞机制是已知的，包括通过其5'非翻译区，microRNA和非编码反义RNA进行转录后调控。BACE1是降低Abeta疗法的主要靶标，但是迄今为止，高亲和力生物利用抑制剂的开发一直是一项重大挑战。

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Function, regulation and therapeutic properties of beta-secretase (BACE1).

beta-Secretase (beta-site amyloid precursor protein cleaving enzyme 1; BACE1) has been identified as the rate limiting enzyme for amyloid-beta-peptide (Abeta) production. Abeta is the major component of amyloid plaques and vascular deposits in Alzheimer's disease (AD) brains and believed to initiate the deadly amyloid cascade. BACE1 is the principle beta-secretase, since its knock-out completely prevents Abeta generation. BACE1 is likely to process a number of different substrates and consequently several independent physiological functions may be exerted by BACE1. Currently the function of BACE1 in myelination is best understood. BACE1 cleaves and activates Neuregulin-1 and is thus directly involved in myelination of the peripheral nervous system during early postnatal development. However, additional physiological functions specifically within the central nervous system are so far less understood. BACE1 is upregulated in at least some AD brains. Multiple cellular mechanisms for BACE1 regulation are known including post-transcriptional regulation via its 5'-untranslated region, microRNA and non-coding anti-sense RNA. BACE1 is a primary target for Abeta lowering therapies, however the development of high affinity bio-available inhibitors has been a major challenge so far.

更新日期：2009-01-20

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