Kandalepas Patty C, Vassar Robert
Northwestern University, Feinberg School of Medicine, Department of Cell & Molecular Biology, 300 E. Superior, Tarry 8-713, IL 60611, Chicago.
Curr Alzheimer Res. 2014;11(5):441-9. doi: 10.2174/1567205011666140604122059.
As the most common neurodegenerative disease, therapeutic avenues for the treatment and prevention of Alzheimer's Disease are highly sought after. The aspartic protease BACE1 is the initiator enzyme for the formation of Aβ, a major constituent of amyloid plaques that represent one of the hallmark pathological features of this disorder. Thus, targeting BACE1 for disease-modifying AD therapies represents a rationale approach. The collective knowledge acquired from investigations of BACE1 deletion mutants and characterization of BACE1 substrates has downstream significance not only for the discovery of AD drug therapies but also for predicting side effects of BACE1 inhibition. Here we discuss the identification and validation of BACE1 as the β-secretase implicated in AD, in addition to information regarding BACE1 cell biology, localization, substrates and potential physiological functions derived from BACE1 knockout models.
作为最常见的神经退行性疾病，治疗和预防阿尔茨海默病的途径备受关注。天冬氨酸蛋白酶β-分泌酶1（BACE1）是淀粉样β蛋白（Aβ）形成的起始酶，Aβ是淀粉样斑块的主要成分，而淀粉样斑块是该疾病标志性病理特征之一。因此，将BACE1作为改变疾病进程的阿尔茨海默病治疗靶点是一种合理的方法。从对BACE1缺失突变体的研究以及对BACE1底物的表征中获得的综合知识，不仅对发现阿尔茨海默病药物疗法具有下游意义，而且对预测BACE1抑制的副作用也具有重要意义。在这里，我们除了讨论从BACE1基因敲除模型中获得的有关BACE1细胞生物学、定位、底物和潜在生理功能的信息外，还将探讨BACE1作为与阿尔茨海默病相关的β-分泌酶的鉴定和验证。
