It has been long believed that cathepsins compensate for each other because of their overlapping substrate specificities. However, there is increasing evidence that disturbance of the normal balance of their enzymatic activities is the first insult in brain aging and age-related diseases. The imbalance of cathepsins may further cause age-related neuropathological changes such as accumulation of autophagic vacuoles and the formation of ceroid-lipofuscin leading to neuronal dysfunction and damage. Leakage of cathepsins due to the fragility of lysosomal membranes during aging also contributes to neurodegeneration. Furthermore, the deficiency of cathepsin D has been recently revealed to provoke a novel type of lysosomal storage disease associated with massive neurodegeneration. In these animals, microglia are activated to initiate inflammatory and cytotoxic responses by binding and phagocytosis of storage neurons. Activated microglia also release some members of cathepsins to induce neuronal death by degrading extracellular matrix proteins. Thus the microglial activation possibly through sensing neuronal storage may also be an important causative factor for neurodegeneration in lysosomal storage diseases and age-related diseases such as Alzheimer's disease. This review describes the pathological roles of neuronal and microglial cathepsins in brain aging and age-related diseases.

中文翻译：

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神经元和小胶质组织蛋白酶在衰老和与年龄有关的疾病中。

长期以来人们一直认为组织蛋白酶由于其重叠的底物特异性而相互补偿。但是，越来越多的证据表明，破坏其酶活性的正常平衡是大脑衰老和与年龄有关的疾病的首发侮辱。组织蛋白酶的失衡可能进一步引起与年龄有关的神经病理学改变，例如自噬泡的积累和类脂磷脂素的形成，从而导致神经元功能障碍和损害。由于衰老期间溶酶体膜的脆弱性导致组织蛋白酶的泄漏也有助于神经变性。此外，近来发现组织蛋白酶D的缺乏引起了与大规模神经变性相关的新型溶酶体贮积病。在这些动物中 小胶质细胞通过储存神经元的结合和吞噬作用被激活以引发炎症反应和细胞毒性反应。活化的小胶质细胞还释放组织蛋白酶的某些成员，通过降解细胞外基质蛋白来诱导神经元死亡。因此，可能通过感测神经元存储而引起的小胶质细胞活化也可能是溶酶体存储疾病和与年龄有关的疾病如阿尔茨海默氏病中神经退行性变的重要原因。这篇综述描述了神经元和小胶质组织蛋白酶在脑衰老和与年龄有关的疾病中的病理作用。因此，可能通过感测神经元存储而引起的小胶质细胞活化也可能是溶酶体存储疾病和与年龄有关的疾病如阿尔茨海默氏病中神经退行性变的重要原因。这篇综述描述了神经元和小胶质组织蛋白酶在脑衰老和与年龄有关的疾病中的病理作用。因此，可能通过感测神经元存储而引起的小胶质细胞活化也可能是溶酶体存储疾病和与年龄有关的疾病如阿尔茨海默氏病中神经退行性变的重要原因。这篇综述描述了神经元和小胶质组织蛋白酶在脑衰老和与年龄有关的疾病中的病理作用。