. Insensitivity to Abeta42-lowering nonsteroidal anti-inflammatory drugs and gamma-secretase inhibitors is common among aggressive presenilin-1 mutations. J Biol Chem. 2007 Aug 24;282(34):24504-13. PubMed.

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  1. In this paper, Czirr and colleagues report that presenilin mutations that cause severe, early onset Alzheimer disease can alter the sensitivity of γ-secretase to inhibitors and modulators. The authors demonstrate this using cell lines and a transgenic mouse model. Since presenilin is not mutated in sporadic Alzheimer disease, one implication from this work is that cell lines and mice carrying presenilin mutations may not be suitable models for evaluating candidate γ-secretase inhibitors and modulators as potential therapeutics for sporadic AD.

    As part of this work, the authors also reexamined the Δ exon 9 mutant of presenilin. They show that, contrary to a previous report, the S290C point mutation that is part of this deletion mutant is not alone responsible for increasing the Aβ42/Aβ40 ratio. Instead, using a series of elegantly designed experiments, they show that the change in Aβ42/40 production results from a synergistic effect of this S290C mutation and the inability of the Δ exon 9 variant to undergo endoproteolysis.