Research Article: Increased expression and altered subcellular distribution of cathepsin B in microglia induce cognitive impairment through oxidative stress and inflammatory response in mice

Date Published: December 21, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Junjun Ni, Zhou Wu, Veronika Stoka, Jie Meng, Yoshinori Hayashi, Christoph Peters, Hong Qing, Vito Turk, Hiroshi Nakanishi.


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.

Partial Text

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 activation of microglia is the main cellular source of oxidation products and proinflammatory mediators in the brain (Hayashi et al., 2008; Pawate, Shen, Fan, & Bhat, 2004). Cathepsin B (CatB, EC, a typical cysteine lysosomal protease, is associated with inflammatory responses by microglia through the production of IL‐1β (Terada et al., 2010). Furthermore, CatB is a potential molecular switch that shifts microglia/macrophages toward the neurotoxic phenotype through autophagic activation of nuclear factor‐κB (NF‐κB; Ni et al., 2015). More recently, CatB has been demonstrated to play a critical role in neuroinflammation and impairment of learning and memory induced by chronic systemic exposure to lipopolysaccharide derived from Porphyromonas gingivalis, the major periodontal bacteria, in middle‐aged mice (Wu et al., 2017).

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. A leakage of CatB into the cytosol may trigger these responses, as there are some reports showing the increased lysosomal membrane permeability and the resultant leakage of lysosomal enzymes during aging (Nakamura et al., 1989; Nakanishi et al., 1997). Furthermore, the immunoreactivity for CatB was markedly increased in the hippocampal microglia of mice during aging (Wu et al., 2017). It is important to note that resident microglia are long‐lived cells that can survive the entire mouse lifespan (Füger et al., 2017). These observations suggest that the fragility of the endosomal/lysosomal system of especially long‐lived microglia is markedly increased during aging. Furthermore, the lysosomal membrane is protected from acidic hydrolases by the lysosome‐specific expression of membrane proteins, such as lysosomal‐associated membrane protein (LAMP) 1 and LAMP2, which are heavily glycosylated and hence resist digestion (Eskelinen, 2006). Therefore, the age‐dependent decrease in the gene expression of these lysosomal membrane proteins is also involved in an age‐dependent increase in the lysosomal membrane permeabilization (Huang, Xu, Pang, Bai, & Yan, 2012).

None declared.

J.N. conducted most of the experiments, analyzed the data, and wrote the manuscript. Z.W. designed and conducted some histological experiments and wrote the manuscript. V.S. analyzed the data. J.M. and Y.H. performed electrophysiological experiments. C.P. and T.V. provided advice about data interpretation. H.Q. provided unpublished reagents/analytic tools. H.N. designed the whole study and wrote the manuscript.




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