Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer's disease

Neuron. 2006 Sep 21;51(6):703-14. doi: 10.1016/j.neuron.2006.07.027.


Alzheimer's disease (AD) may result from the accumulation of amyloid-beta (Abeta) peptides in the brain. The cysteine protease cathepsin B (CatB) is associated with amyloid plaques in AD brains and has been suspected to increase Abeta production. Here, we demonstrate that CatB actually reduces levels of Abeta peptides, especially the aggregation-prone species Abeta1-42, through proteolytic cleavage. Genetic inactivation of CatB in mice with neuronal expression of familial AD-mutant human amyloid precursor protein (hAPP) increased the relative abundance of Abeta1-42, worsening plaque deposition and other AD-related pathologies. Lentivirus-mediated expression of CatB in aged hAPP mice reduced preexisting amyloid deposits, even thioflavin S-positive plaques. Under cell-free conditions, CatB effectively cleaved Abeta1-42, generating C-terminally truncated Abeta peptides that are less amyloidogenic. Thus, CatB likely fulfills antiamyloidogenic and neuroprotective functions. Insufficient CatB activity might promote AD; increasing CatB activity could counteract the neuropathology of this disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid / metabolism*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Peptides / ultrastructure
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Cathepsin B / genetics
  • Cathepsin B / metabolism*
  • Cell Line, Tumor
  • Female
  • Humans
  • Hydrolysis
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Microscopy, Confocal
  • Microscopy, Electron
  • Mutation / genetics
  • Neurites / metabolism
  • Neurites / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Peptide Fragments / metabolism
  • Peptide Fragments / ultrastructure
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology


  • Amyloid
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • Cathepsin B