Cytotoxic mechanisms by M239V presenilin 2, a little-analyzed Alzheimer's disease-causative mutant.
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.
Abe
Yoichiro
Y
Department of Pharmacology, KEIO University School of Medicine, Tokyo, Japan.
Hashimoto
Yuichi
Y
Tomita
Yusuke
Y
Terashita
Kenzo
K
Aiso
Sadakazu
S
Tajima
Hirohisa
H
Niikura
Takako
T
Matsuoka
Masaaki
M
Nishimoto
Ikuo
I
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D051379:Mice; D009154:Mutation / Q000235:genetics; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism*; D009498:Neurotoxins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D010446:Peptide Fragments / Q000494:pharmacology; D053766:Presenilin-2; D011506:Proteins / Q000378:metabolism; D051381:Rats; D014407:Tumor Cells, Cultured; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009498:Neurotoxins; D010446:Peptide Fragments; D053766:Presenilin-2; D011506:Proteins; C092862:amyloid beta-protein (10-43); C427211:humanin; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go