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

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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 Gi/o proteins. We conclude that M146L‐PS1 activates a NOS‐mediated cytotoxic pathway via a novel PTX target.