Evin Genevieve, Barakat Adel
Oxidation Biology Laboratory, Mental Health Research Institute, Florey Institute of Neuroscience and Mental Health, University of Melbourne.
Department of Pathology, University of Melbourne, Parkville, VIC, Australia.
Degener Neurol Neuromuscul Dis. 2014 Jan 22;4:1-19. doi: 10.2147/DNND.S41056. eCollection 2014.
Alzheimer's disease (AD) is the major cause of dementia in the elderly and an unmet clinical challenge. A variety of therapies that are currently under development are directed to the amyloid cascade. Indeed, the accumulation and toxicity of amyloid-β (Aβ) is believed to play a central role in the etiology of the disease, and thus rational interventions are aimed at reducing the levels of Aβ in the brain. Targeting β-site amyloid precursor protein-cleaving enzyme (BACE)-1 represents an attractive strategy, as this enzyme catalyzes the initial and rate-limiting step in Aβ production. Observation of increased levels of BACE1 and enzymatic activity in the brain, cerebrospinal fluid, and platelets of patients with AD and mild cognitive impairment supports the potential benefits of BACE1 inhibition. Numerous potent inhibitors have been generated, and many of these have been proved to lower Aβ levels in the brain of animal models. Over 10 years of intensive research on BACE1 inhibitors has now culminated in advancing half a dozen of these drugs into human trials, yet translating the in vitro and cellular efficacy of BACE1 inhibitors into preclinical and clinical trials represents a challenge. This review addresses the promises and also the potential problems associated with BACE1 inhibitors for AD therapy, as the complex biological function of BACE1 in the brain is becoming unraveled.
阿尔茨海默病（AD）是老年人痴呆的主要病因，也是一项尚未解决的临床挑战。目前正在研发的多种疗法都针对淀粉样蛋白级联反应。的确，淀粉样β蛋白（Aβ）的积累和毒性被认为在该病的病因中起核心作用，因此合理的干预措施旨在降低大脑中Aβ的水平。靶向β-位点淀粉样前体蛋白裂解酶（BACE）-1是一种有吸引力的策略，因为该酶催化Aβ产生的起始和限速步骤。在AD和轻度认知障碍患者的大脑、脑脊液和血小板中观察到BACE1水平和酶活性升高，这支持了抑制BACE1的潜在益处。已经产生了许多强效抑制剂，其中许多已被证明可降低动物模型大脑中的Aβ水平。对BACE1抑制剂进行了10多年的深入研究，目前已有六种此类药物进入人体试验阶段，然而，将BACE1抑制剂的体外和细胞疗效转化为临床前和临床试验仍面临挑战。随着BACE1在大脑中的复杂生物学功能逐渐被揭示，本综述探讨了BACE1抑制剂在AD治疗中的前景以及潜在问题。
