Effect of conjugated linoleic acid, μ-calpain inhibitor, on pathogenesis of Alzheimer's disease

Eunyoung Lee, Ji Eun Eom, Hye Lin Kim, Kyung Hye Baek, Kyu Yeon Jun, Hwa Jung Kim, Minyung Lee, Inhee Mook-Jung, Youngjoo Kwon

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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.

Original languageEnglish
Pages (from-to)709-718
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1831
Issue number4
DOIs
StatePublished - Apr 2013

Keywords

  • Alzheimer's disease
  • Aβ oligomerization
  • Conjugated linoleic acid
  • μ-Calpain inhibitor

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