Nucleus distribution of cathepsin B in senescent microglia promotes brain aging through degradation of sirtuins

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. •Nuclear translocation of cathepsin B with aging relates to neuroinflammation.•Nuclear cathepsin B is responsible for the degradation of nuclear sirtuins during aging.•Microglial cathepsin B–mediated neuroinflammation contributes to neurodegeneration.