title: Effect of conjugated linoleic acid, μ-calpain inhibitor, on pathogenesis of Alzheimer's disease.
abstract: μ-Calpain is a calcium-dependent cysteine protease, which is activated by μM concentration of calcium in vitro. Disrupted intracellular calcium homeostasis leads to hyper-activation of μ-calpain. Hyper-activated μ-calpain enhances the accumulation of β-amyloid peptide by increasing the expression level of β-secretase (BACE1) and induces hyper-phosphorylation of tau along with the formation of neurofibrillary tangle by mediating p35 cleavage into p25, both of which are the major mechanisms of neurodegeneration in Alzheimer's disease (AD). Hence, inhibition of μ-calpain activity is very important in the treatment and prevention of AD. In this study, conjugated linoleic acid (CLA), an eighteen-carbon unsaturated fatty acid, was discovered as a μ-calpain-specific inhibitor. CLA showed neuroprotective effects against neurotoxins such as H2O2 and Aβ1-42 in SH-SY5Y cells, and inhibited Aβ oligomerization/fibrillation and Aβ-induced Zona Occludens-1 degradation. In addition, CLA decreased the levels of proapoptotic proteins, p35 conversion to p25 and tau phosphorylation. These findings implicate CLA as a new core structure for selective μ-calpain inhibitors with neuroprotective effects. CLA should be further evaluated for its potential use as an AD therapeutic agent.
authors.affiliation: College of Pharmacy, Division of Life & Pharmaceutical Sciences, Ewha Womans University, Seoul, 120-750, Republic of Korea.
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Lee
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Eom
authors.forename: Hye-Lin
authors.initials: HL
authors.lastname: Kim
authors.forename: Kyung Hye
authors.initials: KH
authors.lastname: Baek
authors.forename: Kyu-Yeon
authors.initials: KY
authors.lastname: Jun
authors.forename: Hwa-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Minyung
authors.initials: M
authors.lastname: Lee
authors.forename: Inhee
authors.initials: I
authors.lastname: Mook-Jung
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Kwon
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D044243:Linoleic Acids, Conjugated / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D006023:Glycoproteins; D044243:Linoleic Acids, Conjugated; D018696:Neuroprotective Agents; C039304:calpain inhibitors; D016875:tau Proteins; D006861:Hydrogen Peroxide; D002154:Calpain; C449002:mu-calpain