Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, India.
Mini Rev Med Chem. 2022;22(15):2012-2023. doi: 10.2174/1389557522666220214095859.
The lysosomal cysteine protease enzyme, named Cathepsin B, mainly degrades the protein and manages its average turnover in our body. The Cathepsin B active form is mostly present inside the lysosomal part at a cellular level, providing the slightly acidic medium for its activation. Multiple findings on Cathepsin B reveal its involvement in neurons' degeneration and a possible role as a neuronal death mediator in several neurodegenerative diseases. In this review article, we highlight the participation of Cathepsin B in the etiology/progress of AD, along with various other factors. The enzyme is involved in producing neurotoxic Aβ amyloid in the AD brain by acting as the β-secretase enzyme in the regulated secretory pathways responsible for APP processing. Aβ amyloid accumulation and amyloid plaque formation lead to neuronal degeneration, one of the prominent pathological hallmarks of AD. Cathepsin B is also involved in the production of PGlu-Aβ, which is a truncated and highly neurotoxic form of Aβ. Some of the findings also revealed that Cathepsin B specific gene deletion decreases the level of PGlu-Aβ inside the brain of experimental mice. Therefore, neurotoxicity might be considered a new pathological indication of AD due to the involvement of Cathepsin B. It also damages neurons present in the CNS region by producing inflammatory responses and generating mitochondrial ROS. However, Cathepsin B inhibitors, i.e., CA-074, can prevent neuronal death in AD patients. The other natural inhibitors are also equally effective against neuronal damage with higher selectivity. Its synthetic inhibitors are specific for their target; however, they lose their selectivity in the presence of quite a few reducing agents. Therefore, a humanized monoclonal antibody is used as a selective Cathepsin B inhibitor to overcome the problem experienced. The use of Cathepsin B for the treatment of AD and other neurodegenerative diseases could be considered a rational therapeutic target.
溶酶体半胱氨酸蛋白酶酶，称为组织蛋白酶 B，主要降解蛋白质并管理其在我们体内的平均周转率。组织蛋白酶 B 的活性形式主要存在于细胞水平的溶酶体部分，为其激活提供略微酸性的介质。多项关于组织蛋白酶 B 的发现表明其参与神经元退化，并可能在几种神经退行性疾病中作为神经元死亡介质发挥作用。在这篇综述文章中，我们强调了组织蛋白酶 B 在 AD 的病因/进展中的参与，以及其他各种因素。该酶通过在负责 APP 加工的调节分泌途径中充当β-分泌酶酶来参与 AD 大脑中产生神经毒性 Aβ淀粉样蛋白。Aβ 淀粉样蛋白的积累和淀粉样斑块的形成导致神经元退化，这是 AD 的主要病理标志之一。组织蛋白酶 B 还参与 PGlu-Aβ的产生，PGlu-Aβ 是 Aβ 的一种截断的、高度神经毒性形式。一些研究结果还表明，组织蛋白酶 B 特异性基因缺失可降低实验小鼠大脑中 PGlu-Aβ的水平。因此，由于组织蛋白酶 B 的参与，神经毒性可能被认为是 AD 的新病理指标。它还通过产生炎症反应和产生线粒体 ROS 来破坏中枢神经系统 (CNS) 区域中的神经元。然而，组织蛋白酶 B 抑制剂，即 CA-074，可以预防 AD 患者的神经元死亡。其他天然抑制剂对神经元损伤同样有效，选择性更高。其合成抑制剂针对其靶标具有特异性；然而，在存在相当数量的还原剂时，它们会失去选择性。因此，使用人源化单克隆抗体作为选择性组织蛋白酶 B 抑制剂来克服所经历的问题。将组织蛋白酶 B 用于治疗 AD 和其他神经退行性疾病可以被认为是一个合理的治疗靶点。
