BACE inhibitor reduces APP-beta-C-terminal fragment accumulation in axonal swellings of okadaic acid-induced neurodegeneration.
Emerging evidence suggests that not only beta-amyloid but also other amyloid precursor protein (APP) fragments, such as the beta-C-terminal fragment (betaCTF), might be involved in Alzheimer's disease (AD). Treatment of neurons with okadaic acid (OA), a protein phosphatase-2A inhibitor, has been used to induce tau phosphorylation and neuronal death to create a research model of AD. In this study, we analyzed axonopathy and APP regulation in cultured rat neurons treated with OA. After OA treatment, the neurons presented with axonal swellings filled with vesicles, microtubule fragments, and transport molecules such as kinesin and synapsin-I. Western blotting showed that intracellular APP levels were increased and immunocytochemistry using antibodies against the APP C-terminus showed that APP accumulated in the axonal swellings. This APP C-terminus immunoreactivity disappeared when neurons were cotreated with a beta-secretase inhibitor, but not with alpha- or gamma-secretase inhibitors, indicating that the accumulation was primarily composed of APP-betaCTF. These findings provide the first evidence that APP-betaCTF can accumulate in the axons of OA-treated neurons, and may suggest that APP-betaCTF is involved in the pathogenesis of AD.
Yoon
Seung Yong
SY
Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, South Korea.
Choi
Jung Eun
JE
Yoon
Ju Hee
JH
Huh
Jae-Wan
JW
Kim
Dong Hou
DH
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D016282:Aspartic Acid Endopeptidases; D001370:Axonal Transport / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D010450:Endopeptidases / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D046529:Microscopy, Electron, Transmission; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D019319:Okadaic Acid / Q000037:antagonists & inhibitors; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; C441641:amyloid precursor protein carboxyl-terminal fragment gamma; D019319:Okadaic Acid; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat