In this interesting paper, Kukar and colleagues report that many NSAIDs and their derivatives selectively raise Aβ42 and lower Aβ38 secretion. These results are surprising, given the group’s original finding that another subset of NSAIDs do just the opposite, namely, reduce
Aβ42 and increase
Aβ38 production (Weggen et al., 2001). What makes their work even more intriguing is that endogenous isoprenoids, GGPP and FPP, also increase Aβ42 and decrease Aβ38, suggesting that this effect may have physiological relevance. The compounds do not activate RhoA and ROCK, thus excluding protein isoprenylation as a mechanism, but instead appear to act directly on the γ-secretase complex. Importantly, treatment of wild-type and Tg2576 mice with Celecoxib and a novel compound, FT-1, increased cerebral levels of Aβ42 levels but left those of Aβ40 unchanged. Their results raise the potential concern that exposure to similar compounds in the environment may raise Aβ42 in humans and cause AD.
An intriguing aspect of this work is that rather large and diverse sets of compounds...