Department of Biochemistry, Bharathidasan University, Trichy 24, India.
Clin Chim Acta. 2012 Dec 24;414:171-8. doi: 10.1016/j.cca.2012.08.013. Epub 2012 Aug 20.
Targeting BACE1 (β-site APP cleaving enzyme 1 or β-secretase) is the focus of Alzheimer's disease (AD) research because this aspartyl protease is involved in the abnormal production of β amyloid plaques (Aβ), the hallmark of its pathophysiology. Evidence suggests that there is a strong connection between AD and BACE1. As such, strategies to inhibit Aβ formation in the brain should prove beneficial for AD treatment. Aβ, the product of the large type1 trans-membrane protein amyloid precursor protein (APP), is produced in a two-step proteolytic process initiated by BACE1 (β-secretase) and followed by γ-secretase. Due to its apparent rate limiting function, BACE1 appears to be a prime target to prevent Aβ generation in AD. Following its discovery, the BACE1 has been cloned, its structure solved, novel physiologic substrates discovered and numerous inhibitors developed. This review focuses on elucidating the role of BACE1 to facilitate drug development in the treatment of AD.
靶向 BACE1（β-位淀粉样前体蛋白裂解酶 1 或 β-分泌酶）是阿尔茨海默病（AD）研究的重点，因为这种天冬氨酸蛋白酶参与了β淀粉样蛋白斑块（Aβ）的异常产生，这是其病理生理学的标志。有证据表明，AD 与 BACE1 之间存在很强的联系。因此，抑制大脑中 Aβ 形成的策略应该有助于 AD 的治疗。Aβ 是大型跨膜蛋白淀粉样前体蛋白（APP）的产物，在由 BACE1（β-分泌酶）启动的两步蛋白水解过程中产生，随后是γ-分泌酶。由于其明显的限速功能，BACE1 似乎是预防 AD 中 Aβ 生成的主要靶标。BACE1 发现后，已被克隆，其结构已被阐明，新的生理底物已被发现，并且已经开发出许多抑制剂。本综述重点阐述了 BACE1 的作用，以促进 AD 治疗药物的开发。
