The β-Secretase BACE1 in Alzheimer's Disease.
The β-Secretase BACE1 in Alzheimer's Disease.
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阿尔茨海默病中的β-分泌酶BACE1
DOI：
10.1016/j.biopsych.2020.02.001
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发表时间：
2021-04-15
影响因子：
10.6
通讯作者：
Vergallo A
中科院分区：
文献类型：
--
作者：
Hampel H;Vassar R;De Strooper B;Hardy J;Willem M;Singh N;Zhou J;Yan R;Vanmechelen E;De Vos A;Nisticò R;Corbo M;Imbimbo BP;Streffer J;Voytyuk I;Timmers M;Tahami Monfared AA;Irizarry M;Albala B;Koyama A;Watanabe N;Kimura T;Yarenis L;Lista S;Kramer L;Vergallo A
β - 位点淀粉样前体蛋白裂解酶1（BACE1）于1999年首次被克隆和鉴定。它是产生所有单体形式的淀粉样β蛋白（Aβ）所必需的，包括Aβ42，Aβ42会聚集成具有生物活性的构象种类，并可能在阿尔茨海默病（AD）中引发毒性。阿尔茨海默病患者的大脑和体液中BACE1的浓度和活性速率增加，从而支持了BACE1在阿尔茨海默病病理生理学中起关键作用这一假说。因此，BACE1是在阿尔茨海默病早期减缓Aβ产生的主要药物靶点。除了淀粉样蛋白生成途径外，BACE1还有其他可能对突触可塑性和突触内稳态很重要的底物。事实上，种系和成年条件性BACE1基因敲除小鼠表现出复杂的神经学表型。尽管到目前为止进行的BACE1抑制剂临床试验因无效或安全原因而终止，但BACE1仍然是阿尔茨海默病一个经过充分验证的治疗靶点。可能仍会发现一种具有高底物选择性以及更准确的剂量方案、患者群体和疾病阶段的安全有效的化合物。进一步的研究应聚焦于Aβ和BACE1在阿尔茨海默病生理过程和关键病理生理机制中的作用。BACE1和同源物BACE2的功能，以及Aβ在神经元和神经胶质中的生物学特性，值得进一步研究。对BACE1和BACE2基因敲除小鼠进行细胞和分子研究，并结合基于生物标志物的人类研究，将有助于阐明这些重要酶的生物学功能，并确定它们的底物和下游效应。此类研究对于将BACE1抑制作为阿尔茨海默病的一种治疗方法具有关键意义。
BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) was initially cloned and characterized in 1999. It is required for the generation of all monomeric forms of amyloid-β (Aβ), including Aβ42, which aggregates into bioactive conformational species and likely initiates toxicity in Alzheimer’s disease (AD). BACE1 concentrations and rates of activity are increased in AD brains and body fluids, thereby supporting the hypothesis that BACE1 plays a critical role in AD pathophysiology. Therefore, BACE1 is a prime drug target for slowing down Aβ production in early AD. Besides the amyloidogenic pathway, BACE1 has other substrates that may be important for synaptic plasticity and synaptic homeostasis. Indeed, germline and adult conditional BACE1 knockout mice display complex neurological phenotypes. Despite BACE1 inhibitor clinical trials conducted so far being discontinued for futility or safety reasons, BACE1 remains a well-validated therapeutic target for AD. A safe and efficacious compound with high substrate selectivity as well as a more accurate dose regimen, patient population, and disease stage may yet be found. Further research should focus on the role of Aβ and BACE1 in physiological processes and key pathophysiological mechanisms of AD. The functions of BACE1 and the homologue BACE2, as well as the biology of Aβ in neurons and glia, deserve further investigation. Cellular and molecular studies of BACE1 and BACE2 knockout mice coupled with biomarker-based human research will help elucidate the biological functions of these important enzymes and identify their substrates and downstream effects. Such studies will have critical implications for BACE1 inhibition as a therapeutic approach for AD.
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