Hook Vivian Y H, Kindy Mark, Reinheckel Thomas, Peters Christoph, Hook Gregory
Depts of Neurosciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093-0744, USA.
Biochem Biophys Res Commun. 2009 Aug 21;386(2):284-8. doi: 10.1016/j.bbrc.2009.05.131. Epub 2009 Jun 6.
Neurotoxic beta-amyloid (Abeta) peptides participate in Alzheimer's disease (AD); therefore, reduction of Abeta generated from APP may provide a therapeutic approach for AD. Gene knockout studies in transgenic mice producing human Abeta may identify targets for reducing Abeta. This study shows that knockout of the cathepsin B gene in mice expressing human wild-type APP (hAPPwt) results in substantial decreases in brain Abeta40 and Abeta42 by 67% and decreases in levels of the C-terminal beta-secretase fragment (CTFbeta) derived from APP. In contrast, knockout of cathepsin B in mice expressing hAPP with the rare Swedish (Swe) and Indiana (Ind) mutations had no effect on Abeta. The difference in reduction of Abeta in hAPPwt mice, but not in hAPPSwe/Ind mice, shows that the transgenic model can affect cathepsin B gene knockout results. Since most AD patients express hAPPwt, these data validate cathepsin B as a target for development of inhibitors to lower Abeta in AD.
神经毒性β-淀粉样蛋白（Aβ）肽参与阿尔茨海默病（AD）的发生；因此，减少由淀粉样前体蛋白（APP）产生的Aβ可能为AD提供一种治疗方法。在产生人Aβ的转基因小鼠中进行的基因敲除研究可能会确定减少Aβ的靶点。本研究表明，在表达人野生型APP（hAPPwt）的小鼠中敲除组织蛋白酶B基因，可使脑内Aβ40和Aβ42水平大幅降低67%，并使源自APP的C末端β-分泌酶片段（CTFβ）水平降低。相比之下，在表达具有罕见瑞典（Swe）和印第安纳（Ind）突变的hAPP的小鼠中敲除组织蛋白酶B对Aβ没有影响。hAPPwt小鼠而非hAPPSwe/Ind小鼠中Aβ减少的差异表明，转基因模型会影响组织蛋白酶B基因敲除的结果。由于大多数AD患者表达hAPPwt，这些数据证实组织蛋白酶B是开发降低AD中Aβ的抑制剂的一个靶点。
