American Life Science Pharmaceuticals, La Jolla, California (G.H.); Institute of Molecular Medicine and Cell Research, Faculty of Medicine, Albert Ludwigs University, Freiburg, Germany (T.R.); German Cancer Consortium (DKTK) Partner Site Freiburg, Freiburg, Germany (T.R.); German Cancer Research Center (DKFZ), Heidelberg, Germany (T.R); Center for Biological Signaling Studies BIOSS, Albert Ludwigs University, Freiburg, Germany (T.R.); Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, China (J.N.); Department of Aging Science and Pharmacology, OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan (Z.W); Taneja College of Pharmacy, Department of Pharmaceutical Sciences, University of South Florida, Tampa, Florida (M.K.); James A Haley VAMC, Research Service, Tampa, Florida (M.K.); Institute of Molecular Medicine and Cell Research, Faculty of Biology, Albert Ludwigs University, Freiburg, Germany (C.P.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, CA (V.H.); and Department of Neuroscience and Department of Pharmacology, School of Medicine, University of California, La Jolla, CA (V.H.).
American Life Science Pharmaceuticals, La Jolla, California (G.H.); Institute of Molecular Medicine and Cell Research, Faculty of Medicine, Albert Ludwigs University, Freiburg, Germany (T.R.); German Cancer Consortium (DKTK) Partner Site Freiburg, Freiburg, Germany (T.R.); German Cancer Research Center (DKFZ), Heidelberg, Germany (T.R); Center for Biological Signaling Studies BIOSS, Albert Ludwigs University, Freiburg, Germany (T.R.); Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, China (J.N.); Department of Aging Science and Pharmacology, OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan (Z.W); Taneja College of Pharmacy, Department of Pharmaceutical Sciences, University of South Florida, Tampa, Florida (M.K.); James A Haley VAMC, Research Service, Tampa, Florida (M.K.); Institute of Molecular Medicine and Cell Research, Faculty of Biology, Albert Ludwigs University, Freiburg, Germany (C.P.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, CA (V.H.); and Department of Neuroscience and Department of Pharmacology, School of Medicine, University of California, La Jolla, CA (V.H.)
Pharmacol Rev. 2022 Jul;74(3):600-629. doi: 10.1124/pharmrev.121.000527.
Cathepsin B (CTSB) is a powerful lysosomal protease. This review evaluated gene knockout (KO) outcomes for amelioration of brain dysfunctions in neurologic diseases and aging animal models. Deletion of the gene resulted in significant improvements in behavioral deficits, neuropathology, and/or biomarkers in traumatic brain injury, ischemia, inflammatory pain, opiate tolerance, epilepsy, aging, transgenic Alzheimer's disease (AD), and periodontitis AD models as shown in 12 studies. One study found beneficial effects for double and cathepsin S KO mice in a multiple sclerosis model. Transgenic AD models using amyloid precursor protein (APP) mimicking common sporadic AD in three studies showed that KO improved memory, neuropathology, and biomarkers; two studies used APP representing rare familial AD and found no KO effect, and two studies used highly engineered APP constructs and reported slight increases in a biomarker. In clinical studies, all reports found that CTSB enzyme was upregulated in diverse neurologic disorders, including AD in which elevated CTSB was positively correlated with cognitive dysfunction. In a wide range of neurologic animal models, CTSB was also upregulated and not downregulated. Further, human genetic mutation data provided precedence for CTSB upregulation causing disease. Thus, the consilience of data is that gene KO results in improved brain dysfunction and reduced pathology through blockade of CTSB enzyme upregulation that causes human neurologic disease phenotypes. The overall findings provide strong support for CTSB as a rational drug target and for CTSB inhibitors as therapeutic candidates for a wide range of neurologic disorders. SIGNIFICANCE STATEMENT: This review provides a comprehensive compilation of the extensive data on the effects of deleting the cathepsin B () gene in neurological and aging mouse models of brain disorders. Mice lacking the gene display improved neurobehavioral deficits, reduced neuropathology, and amelioration of neuronal cell death and inflammatory biomarkers. The significance of the compelling CTSB evidence is that the data consilience validates CTSB as a drug target for discovery of CTSB inhibitors as potential therapeutics for treating numerous neurological diseases.
组织蛋白酶 B (CTSB) 是一种强大的溶酶体蛋白酶。本综述评估了基因敲除 (KO) 对改善神经疾病和衰老动物模型中脑功能障碍的结果。在 12 项研究中，基因缺失导致创伤性脑损伤、缺血、炎性疼痛、阿片类药物耐受、癫痫、衰老、转基因阿尔茨海默病 (AD) 和牙周炎 AD 模型中的行为缺陷、神经病理学和/或生物标志物显著改善。一项研究发现，多发性硬化症模型中双和组织蛋白酶 S KO 小鼠有有益的影响。三项研究中使用淀粉样前体蛋白 (APP) 模拟常见散发性 AD 的转基因 AD 模型表明，KO 改善了记忆、神经病理学和生物标志物；两项研究使用代表罕见家族性 AD 的 APP，未发现 KO 效应，两项研究使用高度工程化的 APP 构建体，报告生物标志物略有增加。在临床研究中，所有报告都发现 CTSB 酶在多种神经疾病中上调，包括 AD，其中 CTSB 的升高与认知功能障碍呈正相关。在广泛的神经动物模型中，CTSB 也被上调而不是下调。此外，人类遗传突变数据为 CTSB 上调导致疾病提供了先例。因此，数据的一致性表明，通过阻断导致人类神经疾病表型的 CTSB 酶上调，KO 导致改善的脑功能障碍和减少病理学。总体研究结果为 CTSB 作为合理的药物靶点以及 CTSB 抑制剂作为广泛的神经障碍治疗候选物提供了强有力的支持。意义陈述：本综述提供了广泛的神经和衰老小鼠脑疾病模型中删除组织蛋白酶 B (CTSB) 基因的影响的全面综述。缺乏基因的小鼠显示出改善的神经行为缺陷、减少的神经病理学、神经元细胞死亡和炎症生物标志物的改善。CTSB 证据的重要意义在于，数据的一致性验证了 CTSB 作为药物靶点的合理性，为发现 CTSB 抑制剂作为治疗多种神经疾病的潜在治疗方法提供了依据。
