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

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.

► CLA is a potent, selective, and cell permeable non-peptidic μ-calpain inhibitor.
► CLA increased the viability of neurotoxin-treated SH-SY5Y cells.
► CLA directly scavenged ROS generation and prevented Aβ-induced ZO-1 degradation.
► CLA has a neuroprotective effect against H2O2 in cells and rat brain lysate.
► Docking studies showed that CLA fitted into the active site of μ-calpain.