Reduction of mint-1, mint-2, and APP overexpression in okadaic acid-treated neurons.
Treatment of neurons with okadaic acid, a protein phosphatase-2A inhibitor, has been used to induce tau phosphorylation and neuronal death, and to create a research model of Alzheimer's disease. Amyloid precursor protein (APP) is the precursor protein of the beta-amyloid peptide that accumulates in extracellular plaques in Alzheimer's disease. Several studies have shown that mint-1 (munc18-interacting protein 1) and mint-2 bind to the YENPTY motif in the cytoplasmic domain of APP and inhibit processing of APP to beta-amyloid peptide. Here, we report that, upon neurodegeneration with okadaic acid, mint-1 and mint-2 levels were reduced by proteolytic cleavage, and that these changes were followed by increases in APP levels. We also show that the mint-1 and mint-2 cleavage and APP overexpression were prevented by calpain inhibitor-I and inhibitor-II. These results indicate that mint cleavage might play a role in the pathophysiology of Alzheimer's disease.
Yoon
Seungyong
S
Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea.
Choi
Jungeun
J
Haam
Juhee
J
Choe
Han
H
Kim
DongHou
D
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism* / Q000503:physiopathology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006023:Glycoproteins / Q000378:metabolism / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D019319:Okadaic Acid; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology; D051381:Rats
D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C513071:Apba1 protein, rat; C109650:Apba2 protein, rat; D015820:Cadherins; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009842:Oligopeptides; C039304:calpain inhibitors; C069861:calpain inhibitor 2; D019319:Okadaic Acid; D002154:Calpain