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...  Read more

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 appear to directly bind to the γ-secretase complex and modulate the cleavage site on APP. This suggests that γ-secretase may be quite sensitive to conformational changes. Indeed, the authors propose that their compounds mimic FAD mutations, and it is likely that FAD mutations have an effect, although probably small, on γ-secretase conformation. Slight conformational changes could subtly shift the relative positions of APP and the γ-secretase active site, and thus alter the spectrum of Aβ species that are generated. While the physiological relevance of Aβ remains unknown, one could speculate that the different Aβ isoforms may have specific biological functions. If so, the isoprenoids may be the endogenous modulators of Aβ isoforms by acting directly on γ-secretase to adjust the Aβ population to suit particular physiological requirements.

Accumulating evidence implicates a role for isoprenoids in APP and Aβ metabolism. Indeed, our recent results (Cole et al., in press) demonstrate that low isoprenoid levels (induced by statin treatment) cause the intracellular accumulation of Aβ. We attribute this effect to reduced isoprenylation of small GTPases (e.g., rhos and rabs) that are required for vesicular transport. In contrast, Kukar et al. raised isoprenoid levels in the cell and observed the reciprocal increase and decrease in Aβ42 and Aβ38, respectively. We propose that isoprenoids may be functioning in two separate pathways, depending on their concentrations in the cell: At low concentrations, isoprenoids may primarily affect the activity of small GTPases that in turn influence Aβ trafficking, while at high concentrations, they may directly modulate the γ-secretase complex to alter Aβ isoform balance. The cellular effects of the isoprenoids are clearly complex, and further studies are required to investigate these hypotheses and determine the multifaceted actions of the isoprenoids in APP and Aβ metabolism.

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