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

Junjun Ni, Zhou Wu, Veronika Stoka, Jie Meng, Yoshinori Hayashi, Christoph Peters, Hong Qing, Vito Turk, Hiroshi Nakanishi

研究成果: ジャーナルへの寄稿記事

3 引用 (Scopus)

抄録

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.

元の言語英語
記事番号e12856
ジャーナルAging cell
18
発行部数1
DOI
出版物ステータス出版済み - 2 1 2019

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Cathepsin B
Microglia
Oxidative Stress
Reactive Oxygen Species
Mitochondria
leucylleucine
Lysosomes
Mitochondrial DNA
Innate Immunity
Cytosol
Cognitive Dysfunction
Pharmacology
Injections

All Science Journal Classification (ASJC) codes

  • Ageing
  • Cell Biology

これを引用

Increased expression and altered subcellular distribution of cathepsin B in microglia induce cognitive impairment through oxidative stress and inflammatory response in mice. / Ni, Junjun; Wu, Zhou; Stoka, Veronika; Meng, Jie; Hayashi, Yoshinori; Peters, Christoph; Qing, Hong; Turk, Vito; Nakanishi, Hiroshi.

:: Aging cell, 巻 18, 番号 1, e12856, 01.02.2019.

研究成果: ジャーナルへの寄稿記事

Ni, Junjun ; Wu, Zhou ; Stoka, Veronika ; Meng, Jie ; Hayashi, Yoshinori ; Peters, Christoph ; Qing, Hong ; Turk, Vito ; Nakanishi, Hiroshi. / Increased expression and altered subcellular distribution of cathepsin B in microglia induce cognitive impairment through oxidative stress and inflammatory response in mice. :: Aging cell. 2019 ; 巻 18, 番号 1.
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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.",
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T1 - Increased expression and altered subcellular distribution of cathepsin B in microglia induce cognitive impairment through oxidative stress and inflammatory response in mice

AU - Ni, Junjun

AU - Wu, Zhou

AU - Stoka, Veronika

AU - Meng, Jie

AU - Hayashi, Yoshinori

AU - Peters, Christoph

AU - Qing, Hong

AU - Turk, Vito

AU - Nakanishi, Hiroshi

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

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