title: CA-074Me, a cathepsin B inhibitor, decreases APP accumulation and protects primary rat cortical neurons treated with okadaic acid.
abstract: Upregulation of the lysosomal system has been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). But the exact role of this system remains unknown. Okadaic acid (OA), a protein phosphatase-2A inhibitor, increases tau phosphorylation, β-amyloid deposition, and neuronal cell death, which are the pathological hallmarks of AD. To investigate the role of lysosomal activation in AD brain cells, cultured neurons were treated with OA and assessed lysosomal morphology and enzyme activity and the protective effect of cathepsin B, D, or L inhibitors. It was found that although it induced lysosomal swelling and enzyme activation, OA did not induce lysosomal rupture. While inhibition of cathepsin D and L failed to protect neurons from OA-induced cell death, CA074-Me, a cathepsin B inhibitor, conferred a protective effect. Interestingly, CA-074Me reduced amyloid precursor protein (APP) accumulation and α-spectrin cleavage, similar to the effect of calpain inhibition.
authors.affiliation: Department of Anatomy and Cell Biology, Cell Dysfunction Research Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Kwangmin
authors.initials: K
authors.lastname: Cho
authors.forename: Seung Yong
authors.initials: SY
authors.lastname: Yoon
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Choi
authors.forename: Hoe Jin
authors.initials: HJ
authors.lastname: Kang
authors.forename: He Yoon
authors.initials: HY
authors.lastname: Jang
authors.forename: Dong-Hou
authors.initials: DH
authors.lastname: Kim
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D004151:Dipeptides / Q000008:administration & dosage*; D015536:Down-Regulation / Q000187:drug effects; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000008:administration & dosage; D019319:Okadaic Acid; D051381:Rats; D016896:Treatment Outcome
chemical_list: D016564:Amyloid beta-Protein Precursor; C400541:CA 074 methyl ester; D004151:Dipeptides; D018696:Neuroprotective Agents; D019319:Okadaic Acid; D002401:Cathepsin B; C533916:Ctsb protein, rat
keywords: Alzheimer's disease; CA074-Me; Lysosome; Okadaic acid