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

Biochim Biophys Acta Proteins Proteom. 2020 Aug;1868(8):140428. doi: 10.1016/j.bbapap.2020.140428. Epub 2020 Apr 17.


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.

Keywords: Active site binding; Alzheimer's disease (AD); Behaviors; Biomarker; Brain; Cathepsin B; Cognition; Gene knockout; Human brain; Inhibitors; Lysosomal leakage; Memory; Neurodegeneration; Pathology; Traumatic brain injury (TBI).

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Adult
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / enzymology*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology
  • Animals
  • Brain / drug effects
  • Brain / enzymology*
  • Brain / pathology
  • Brain Injuries, Traumatic / drug therapy
  • Brain Injuries, Traumatic / enzymology*
  • Brain Injuries, Traumatic / genetics
  • Brain Injuries, Traumatic / pathology
  • Cathepsin B / antagonists & inhibitors
  • Cathepsin B / genetics*
  • Cathepsin B / metabolism
  • Cell Death / drug effects
  • Cell Death / genetics
  • Child
  • Cytosol / drug effects
  • Cytosol / enzymology
  • Disease Models, Animal
  • Fetus
  • Gene Expression Regulation
  • Humans
  • Infant
  • Lysosomes / drug effects
  • Lysosomes / enzymology
  • Molecular Targeted Therapy
  • Neurocognitive Disorders / drug therapy
  • Neurocognitive Disorders / enzymology*
  • Neurocognitive Disorders / genetics
  • Neurocognitive Disorders / pathology
  • Neurons / drug effects
  • Neurons / enzymology*
  • Neurons / pathology
  • Neuroprotective Agents / therapeutic use
  • Signal Transduction


  • Neuroprotective Agents
  • CTSB protein, human
  • Cathepsin B