Cathepsin B (CatB) leakage from the lysosome into the cytosol in senescent microglia is associated with cognitive impairment. However, whether cellular compartmental translocation of CatB is associated with brain aging remains unclear. In the present study, increased CatB was found in the nucleus of CatB-overexpressed microglia followed by L-leucyl-L-leucine methyl ester, a lysosome-destabilizing reagent, and in the nuclear fraction of the cortex and hippocampus from aged mice. Moreover, CatB enzymatic activity examination showed the nuclear CatB exhibited the proteolytic activity to cleave its specific substrates. The amount of sirtuin1 (Sirt1), Sirt6, Sirt7, and p-Sirt1 was decreased in the cortical lysates from aged mice, in parallel with increased expression of proinflammatory mediators, which were diminished by CatB deficiency. Furthermore, intralateral ventricle administration of microglia overexpressed CatB, and treatment with L-leucyl-L-leucine methyl ester induced cognitive impairment in middle-aged mice. These observations suggest that the increase and nucleus translocation of CatB in senescent microglia were involved in the degradation of nuclear Sirts, which induced proinflammatory responses, resulting in cognition impairment.

中文翻译：

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衰老小胶质细胞中组织蛋白酶 B 的细胞核分布通过降解 Sirtuins 促进脑衰老

在衰老的小胶质细胞中，组织蛋白酶 B (CatB) 从溶酶体泄漏到细胞质中与认知障碍有关。然而，CatB 的细胞区室易位是否与脑老化有关仍不清楚。在本研究中，在 CatB 过表达的小胶质细胞的细胞核中发现了增加的 CatB，随后是 L-亮氨酰-L-亮氨酸甲酯（一种溶酶体不稳定试剂），以及老年小鼠皮层和海马的核部分。此外，CatB 酶活性检测表明，细胞核 CatB 表现出蛋白水解活性以切割其特定底物。Sirtuin1 (Sirt1)、Sirt6、Sirt7 和 p-Sirt1 在来自老年小鼠的皮质裂解物中的量减少，同时促炎介质的表达增加，后者因 CatB 缺乏而减少。此外，小胶质细胞过表达 CatB 的侧脑室内给药和 L-亮氨酰-L-亮氨酸甲酯治疗诱导中年小鼠的认知障碍。这些观察结果表明，衰老小胶质细胞中 CatB 的增加和细胞核易位参与了核 Sirts 的降解，从而诱导了促炎反应，导致认知障碍。