{"title":"β-位点淀粉样蛋白前体蛋白切割酶1抑制剂治疗阿尔茨海默病的关键分析。","authors":"Genevieve Evin, Adel Barakat","doi":"10.2147/DNND.S41056","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":11147,"journal":{"name":"Degenerative Neurological and Neuromuscular Disease","volume":"4 ","pages":"1-19"},"PeriodicalIF":0.0000,"publicationDate":"2014-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/DNND.S41056","citationCount":"5","resultStr":"{\"title\":\"Critical analysis of the use of β-site amyloid precursor protein-cleaving enzyme 1 inhibitors in the treatment of Alzheimer's disease.\",\"authors\":\"Genevieve Evin, Adel Barakat\",\"doi\":\"10.2147/DNND.S41056\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":11147,\"journal\":{\"name\":\"Degenerative Neurological and Neuromuscular Disease\",\"volume\":\"4 \",\"pages\":\"1-19\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2014-01-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.2147/DNND.S41056\",\"citationCount\":\"5\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Degenerative Neurological and Neuromuscular Disease\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.2147/DNND.S41056\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2014/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Degenerative Neurological and Neuromuscular Disease","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.2147/DNND.S41056","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2014/1/1 0:00:00","PubModel":"eCollection","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 5
摘要
阿尔茨海默病(AD)是老年痴呆症的主要病因,也是一个尚未解决的临床挑战。目前正在开发的各种治疗方法都是针对淀粉样蛋白级联的。事实上,淀粉样蛋白-β (a β)的积累和毒性被认为在该疾病的病因中起着核心作用,因此合理的干预措施旨在降低大脑中a β的水平。靶向β位点淀粉样蛋白前体蛋白切割酶(BACE)-1是一种有吸引力的策略,因为这种酶催化了Aβ生产的初始和限速步骤。观察到AD和轻度认知障碍患者的大脑、脑脊液和血小板中BACE1水平和酶活性升高,支持BACE1抑制的潜在益处。已经产生了许多有效的抑制剂,其中许多已被证明可以降低动物模型大脑中的Aβ水平。经过10多年对BACE1抑制剂的深入研究,目前已有6种此类药物进入人体试验,但将BACE1抑制剂的体外和细胞功效转化为临床前和临床试验仍是一个挑战。随着BACE1在大脑中复杂的生物学功能逐渐被揭示,本文综述了BACE1抑制剂在AD治疗中的前景和潜在问题。
Critical analysis of the use of β-site amyloid precursor protein-cleaving enzyme 1 inhibitors in the treatment of Alzheimer's disease.
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.