title: Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer's disease.
abstract: 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.
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco, 1650 Owens Street, 94158, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Mueller-Steiner
authors.forename: Yungui
authors.initials: Y
authors.lastname: Zhou
authors.forename: Hideaki
authors.initials: H
authors.lastname: Arai
authors.forename: Erik D
authors.initials: ED
authors.lastname: Roberson
authors.forename: Binggui
authors.initials: B
authors.lastname: Sun
authors.forename: Jennifer
authors.initials: J
authors.lastname: Chen
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Guiqiu
authors.initials: G
authors.lastname: Yu
authors.forename: Luke
authors.initials: L
authors.lastname: Esposito
authors.forename: Lennart
authors.initials: L
authors.lastname: Mucke
authors.forename: Li
authors.initials: L
authors.lastname: Gan
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000648:ultrastructure; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D006868:Hydrolysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D009154:Mutation / Q000235:genetics; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism / Q000648:ultrastructure; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D002401:Cathepsin B