Neurotoxic mechanisms triggered by Alzheimer's disease-linked mutant M146L presenilin 1: involvement of NO synthase via a novel pertussis toxin target.
While it has been reported that familial Alzheimer's disease (FAD)-linked mutants of amyloid precursor protein (APP) and presenilin (PS)2 induce neuronal cytotoxicity in a manner sensitive to antioxidant and pertussis toxin (PTX), little of the mechanism for PS1-mediated neuronal cell death has been characterized. We previously found that multiple mechanisms, different in detail, underlie cytotoxicities by two FAD-linked mutants of APP, using neuronal cells with an ecdysone-controlled expression system. Here we report that this system revealed that (i) low expression of FAD-linked M146L-PS1 caused neuronal cell death, whereas that of wild-type (wt)PS1 did not; (ii) mutation-specific cytotoxicity by M146L-PS1 was sensitive to antioxidant glutathione-ethyl-ester and resistant to Ac-DEVD-CHO; (iii) cytotoxicity by higher expression of wtPS1 was resistant to both; and (iv) cytotoxicity by M146L-PS1 was inhibited by PTX. It was also highly likely that the involved superoxide-generating enzyme was nitric oxide synthase (NOS), and that the PTX-sensitive cytotoxic signal by M146L-PS1 was mediated by none of the G(i/o) proteins. We conclude that M146L-PS1 activates a NOS-mediated cytotoxic pathway via a novel PTX target.
Hashimoto
Yuichi
Y
Department of Pharmacology and Neurosciences, KEIO University School of Medicine, Tokyo, Japan.
Ito
Yuko
Y
Arakawa
Erika
E
Kita
Yoshiko
Y
Terashita
Kenzo
K
Niikura
Takako
T
Nishimoto
Ikuo
I
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D037342:Pertussis Toxin; D053764:Presenilin-1; D011837:Radiation-Protective Agents / Q000494:pharmacology; D051381:Rats; D014407:Tumor Cells, Cultured; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D016564:Amyloid beta-Protein Precursor; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D009498:Neurotoxins; D009842:Oligopeptides; D053764:Presenilin-1; D011837:Radiation-Protective Agents; D010566:Virulence Factors, Bordetella; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; D019323:omega-N-Methylarginine; C042431:S-ethyl glutathione; D019001:Nitric Oxide Synthase; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D005978:Glutathione; D019331:NG-Nitroarginine Methyl Ester