Marlow Laura, Cain Melissa, Pappolla Miguel A, Sambamurti Kumar
Medical University of South Carolina, Charleston, SC 29425, USA.
J Mol Neurosci. 2003;20(3):233-9. doi: 10.1385/JMN:20:3:233.
An integral membrane aspartyl protease, BACE, is responsible for beta-secretase processing of the beta-amyloid precursor protein (APP) to the large secreted sAPPbeta and membrane-bound CTFbeta of 99 residues. CTFbeta is subsequently cleaved within the membrane by gamma-secretase to the amyloid beta protein (Abeta) that is deposited in the Alzheimer's disease (AD) brain. In this manuscript, we argue that BACE is not limiting for Abeta production and report the existence of a high molecular weight complex of BACE that is more active than the monomer. We also present evidence that the BACE complex is enriched in lipid raft fractions prepared from brain membranes. These findings support the hypothesis that cleavage by BACE is limited by trafficking of APP (<10%) to a lipid raft-derived compartment containing the BACE complex. In addition, the localization of the BACE complex to lipid rafts can explain previous findings that cholesterol and glycosylphosphatidylinositol (GPI)-anchored proteins are necessary for beta-secretase processing of APP. We propose that the BACE complex is a better drug target than the monomer for specific inhibition of Abeta biogenesis.
一种整合膜天冬氨酸蛋白酶BACE，负责将β-淀粉样前体蛋白（APP）进行β-分泌酶切割，生成大量分泌型sAPPβ和99个残基的膜结合CTFβ。随后，CTFβ在膜内被γ-分泌酶切割成淀粉样β蛋白（Aβ），该蛋白沉积在阿尔茨海默病（AD）患者的大脑中。在本论文中，我们认为BACE并非Aβ生成的限制因素，并报道了存在一种分子量比单体形式更具活性的BACE高分子量复合物。我们还提供证据表明，BACE复合物在从脑膜制备的脂筏组分中富集。这些发现支持了这样一种假说，即BACE的切割受APP转运至含有BACE复合物的脂筏来源区室的限制（<10%）。此外，BACE复合物定位于脂筏可以解释先前的研究结果，即胆固醇和糖基磷脂酰肌醇（GPI）锚定蛋白对于APP的β-分泌酶切割是必需的。我们提出，BACE复合物比单体形式是更适合用于特异性抑制Aβ生成的药物靶点。
