Abstract
During normal aging, innate immunity progresses to a chronic state. However, how oxidative stress and chronic neuroinflammation arise during aging remains unclear. In this study, we found that genetic ablation of cathepsin B (CatB) in mice significantly reduced the generation of reactive oxygen species (ROS) and neuroinflammation and improved cognitive impairment during aging. In cultured microglia, pharmacological inhibition of CatB significantly reduced the generation of mitochondria‐derived ROS and proinflammatory mediators induced by L‐leucyl‐L‐leucine methyl ester (LLOMe), a lysosome‐destabilizing agent. In the CatB‐overexpressing microglia after treatment with LLOMe, which mimicked the aged microglia, CatB leaked in the cytosol is responsible for the degradation of the mitochondrial transcription factor A (TFAM), resulting in the increased generation of mitochondria‐derived ROS and proinflammatory mediators through impaired mtDNA biosynthesis. Furthermore, intralateral ventricle injection of LLOMe‐treated CatB‐overexpressing microglia induced cognitive impairment in middle‐aged mice. These results suggest that the increase and leakage of CatB in microglia during aging are responsible for the increased generation of mitochondria‐derived ROS and proinflammatory mediators, culminating in memory impairment.
Highlights
It is widely believed that oxidative stress and inflammation are major causative factors for the progressive decline in motor and cognitive functions that occur during normal aging in humans and animals (Forster et al, 1996; Navarro, Sanchez Del Pino, Gomez, Peralta, & Boveris, 2002)
To validate the mechanism underlying the lysosomal leakage of cathepsin B (CatB) and mitochondrial reactive oxygen species (ROS) generation, we further examined the possible involvement of CatB in the oxidative and inflammatory responses following treatment with rotenone, which blocks the complex I ubiquinone pathway of the mitochondrial electron transport chain (a)
CatB increased in the hippocampal microglia during aging is responsible for age‐dependent increase in oxidative stress, inflammatory responses, and impairment of learning and memory
Summary
It is widely believed that oxidative stress and inflammation are major causative factors for the progressive decline in motor and cognitive functions that occur during normal aging in humans and animals (Forster et al, 1996; Navarro, Sanchez Del Pino, Gomez, Peralta, & Boveris, 2002). The overexpression of human TFAM in mice significantly inhibits age‐dependent accumulation of mtDNA damage in microglia, resulting in a decrease in the production of ROS and the subsequent activation of NF‐κB‐mediated inflammatory responses and thereby leading to the improvement of age‐dependent motor and memory decline (Hayashi et al, 2008; Nakanishi & Wu, 2009). It is interesting to note that the overexpression of TFAM and genetic depletion of CatB exhibit similar cellular and behavioral phenotypes in mice during aging, including improvement of excessive neuroinflammatory responses, oxidative stress, and memory decline (Hayashi et al, 2008; Wu et al, 2017). We have provided evidence that CatB enhances oxidative stress and inflammatory response in microglia by proteolytic degradation of TFAM after leakage into the cytosol
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