| Cytotoxic mechanisms by M239V presenilin 2, a little-analyzed Alzheimer's disease-causative mutant. | |
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MedLine Citation:
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PMID: 15264228 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Although neurotoxic functions are well characterized in familial Alzheimer's disease (FAD)-linked N141I mutant of presenilin (PS)2, little has been known about M239V-PS2, another established FAD-causative mutant. We found that expression of M239V-PS2 caused neuronal cytotoxicity. M239V-PS2 exerted three forms of cytotoxicity: one was sensitive to both an antioxidant glutathione-ethyl-ester (GEE) and a caspase inhibitor Ac-DEVD-CHO (DEVD); the second was sensitive to GEE but resistant to DEVD; and the third was resistant to both. The GEE/DEVD-sensitive cytotoxicity by M239V-PS2 was likely through NADPH oxidase and the GEE-sensitive/DEVD-resistant cytotoxicity through xanthine oxidase (XO). Both mechanisms by M239V-PS2 were suppressed by pertussis toxin (PTX) and were mediated by Galpha(o), but not by Galpha(i). Although Abeta1-43 itself induced no cytotoxicity, Abeta1-43 potentiated all three components of M239V-PS2 cytotoxicity. As these cytotoxic mechanisms by M239V-PS2 are fully shared with N141I-PS2, they are most likely implicated in the pathomechanism of FAD by PS2 mutations. Notably, cytotoxicity by M239V-PS2 could be inhibited by the combination of two clinically usable inhibitors of superoxide-generating enzymes, apocynin and oxypurinol. |
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Authors:
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Yoichiro Abe; Yuichi Hashimoto; Yusuke Tomita; Kenzo Terashita; Sadakazu Aiso; Hirohisa Tajima; Takako Niikura; Masaaki Matsuoka; Ikuo Nishimoto |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of neuroscience research Volume: 77 ISSN: 0360-4012 ISO Abbreviation: J. Neurosci. Res. Publication Date: 2004 Aug |
Date Detail:
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Created Date: 2004-07-20 Completed Date: 2004-10-04 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 7600111 Medline TA: J Neurosci Res Country: United States |
Other Details:
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Languages: eng Pagination: 583-95 Citation Subset: IM |
Copyright Information:
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Copyright 2004 Wiley-Liss, Inc. |
Affiliation:
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Department of Pharmacology, KEIO University School of Medicine, Tokyo, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Alzheimer Disease
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genetics,
metabolism* Amyloid beta-Protein / pharmacology Animals Antioxidants / pharmacology Enzyme Inhibitors / pharmacology GTP-Binding Protein alpha Subunits, Gi-Go / genetics, metabolism Intracellular Signaling Peptides and Proteins Membrane Proteins / genetics, metabolism*, toxicity* Mice Mutation / genetics NADPH Oxidase / antagonists & inhibitors, metabolism Nerve Degeneration / genetics, metabolism* Neurotoxins / genetics, metabolism*, toxicity* Peptide Fragments / pharmacology Presenilin-2 Proteins / metabolism Rats Tumor Cells, Cultured Xanthine Oxidase / antagonists & inhibitors, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Amyloid beta-Protein; 0/Antioxidants; 0/Enzyme Inhibitors; 0/Intracellular Signaling Peptides and Proteins; 0/Membrane Proteins; 0/Neurotoxins; 0/Peptide Fragments; 0/Presenilin-2; 0/Proteins; 0/amyloid beta-protein (10-43); 0/humanin; EC 1.17.3.2/Xanthine Oxidase; EC 1.6.3.1/NADPH Oxidase; EC 3.6.5.1/GTP-Binding Protein alpha Subunits, Gi-Go |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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