Cathepsin B in neurodegeneration of Alzheimer's disease, traumatic brain injury, and related brain disorders

Investigations of Alzheimer's disease (AD), traumatic brain injury (TBI), and related brain disorders have provided extensive evidence for involvement of cathepsin B, a lysosomal cysteine protease, in mediating the behavioral deficits and neuropathology of these neurodegenerative diseases. This...

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Veröffentlicht in:Biochimica et biophysica acta. Proteins and proteomics 2020-08, Vol.1868 (8), p.140428-140428, Article 140428
Hauptverfasser: Hook, Vivian, Yoon, Michael, Mosier, Charles, Ito, Gen, Podvin, Sonia, Head, Brian P., Rissman, Robert, O'Donoghue, Anthony J., Hook, Gregory
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Sprache:eng
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Zusammenfassung:Investigations of Alzheimer's disease (AD), traumatic brain injury (TBI), and related brain disorders have provided extensive evidence for involvement of cathepsin B, a lysosomal cysteine protease, in mediating the behavioral deficits and neuropathology of these neurodegenerative diseases. This review integrates findings of cathepsin B regulation in clinical biomarker studies, animal model genetic and inhibitor evaluations, structural studies, and lysosomal cell biological mechanisms in AD, TBI, and related brain disorders. The results together indicate the role of cathepsin B in the behavioral deficits and neuropathology of these disorders. Lysosomal leakage occurs in AD and TBI, and related neurodegeneration, which leads to the hypothesis that cathepsin B is redistributed from the lysosome to the cytosol where it initiates cell death and inflammation processes associated with neurodegeneration. These results together implicate cathepsin B as a major contributor to these neuropathological changes and behavioral deficits. These findings support the investigation of cathepsin B as a potential drug target for therapeutic discovery and treatment of AD, TBI, and TBI-related brain disorders. •Cathepsin B is elevated in human Alzheimer's disease (AD) and traumatic brain injury (TBI) patients, and correlates with behavioral and injury outcomes•Inhibition of cathepsin B in AD and TBI animal models results in alleviation of cognitive and behavioral deficits with improvement in neuropathology•Preprocathepsin B undergoes processing to generate mature cathepsin B, which can be selectively inhibited by CA-074•The occluding loop of cathepsin B regulates dipeptidylcarboxypeptidase and endopeptidase activities of cathepsin B•Lysosomal leakage of cathepsin B to the cytosol participates in cell death and inflammation of AD, TBI, and related brain disorders
ISSN:1570-9639
1878-1454
DOI:10.1016/j.bbapap.2020.140428