PMID: 11905990Mar 22, 2002Paper

Neurotoxic mechanisms triggered by Alzheimer's disease-linked mutant M146L presenilin 1: involvement of NO synthase via a novel pertussis toxin target

Journal of Neurochemistry
Yuichi HashimotoI Nishimoto

Abstract

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.

Citations

Apr 27, 2004·Trends in Molecular Medicine·Ikuo NishimotoTakako niikura
Mar 26, 2003·Nihon Ronen Igakkai zasshi. Japanese journal of geriatrics·Takako NiikuraIkuo Nishimoto
Apr 22, 2005·Journal of Insect Science·R Lafont, L Dinan
Sep 1, 2007·Expert Opinion on Drug Discovery·Takako Niikura
May 7, 2004·The European Journal of Neuroscience·Yuichi HashimotoIkuo Nishimoto
Jul 12, 2005·Life Sciences·Yuichi HashimotoMasaaki Matsuoka
Jun 16, 2004·Journal of Neuroscience Research·Takako NiikuraIkuo Nishimoto
Jun 2, 2006·Neuroreport·Yitshak I FrancisDavid S Latchman
Aug 26, 2006·The European Journal of Neuroscience·Gerly A C BritoRonaldo A Ribeiro
Dec 14, 2004·Cell Death and Differentiation·H KadowakiH Ichijo
Feb 4, 2003·Journal of Neurochemistry·Yuichi HashimotoIkuo Nishimoto
Feb 3, 2004·The Journal of Biological Chemistry·Yuichi HashimotoIkuo Nishimoto
Oct 23, 2002·Journal of Neuroscience Research·Takako NiikuraIkuo Nishimoto
Mar 8, 2006·Free Radical Biology & Medicine·Katrin SchuesselAnne Eckert
Jan 2, 2007·Neuroscience Letters·Yitshak I FrancisDavid S Latchman

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