How NSAIDs might prevent Alzheimer's disease

Abstract

Researchers have discovered how some non-steroidal anti-inflammatory drugs (NSAIDs) specifically reduce the conversion of amyloid precursor protein (APP) by secretase to fibrillogenic A 42. A subset of NSAIDS, they report, changes the conformation of presenilin 1, the active site of the -secretase complex. The technique used in the study could be used to discover other drugs that work in the same way but, warns lead author Alberto Lleo (Massachusetts General Hospital Charlestown, MA, USA), “only clinical trials can ultimately tell us which, if any, NSAIDs can prevent Alzheimer’s disease”. Epidemiological evidence accrued since the late 1980s suggests that people who regularly take NSAIDs for other disorders, such as arthritis, have a reduced risk of Alzheimer’s disease. At first, NSAIDs were thought to work by reducing inflammation but in 2001, Edward Koo (University of California San Diego, La Jolla, CA, USA), Todd Golde (Mayo Clinic, Jacksonville, FL, USA), and others reported that some NSAIDs reduced A 42 production in cultured cells and mouse brains. To find out how NSAIDs reduce A 42 production, Lleo and colleagues used fluorescence lifetime imaging (FLIM). When two fluorophores are in close proximity, explains Lleo, fluorescence energy is transferred from the donor to the acceptor fluorophore. The lifetime of the donor fluorophore depends on how close the two fluorophores are: the nearer they are, the shorter the donor’s lifetime. Lleo and co-workers show that the NSAIDs that reduce A 42 production change the distance between APP and presenilin 1 in vitro. Then, by putting fluorophores at either end of presenilin 1, they show that these NSAIDs change the shape of presenilin 1 in vitro and in the brains of mice treated acutely with NSAIDs (Nat Med 2004; 10: 1065–66). “The idea that NSAIDs might change the conformation of secretase is not new, but this is a lovely demonstration of how imaging techniques can be used to look at molecular events”, comments Koo. Both Koo and Golde note that the NSAID concentrations that change presenilin’s conformation in the brain are below those needed to reduce A 42 concentrations in tissue culture. “This supports the notion that NSAIDs are concentrated in the compartments of the brain where secretase resides”, says Golde. But, Lleo warns, “the NSAID doses that we gave to mice were five times higher than those routinely given to people. We now need to find out whether lower NSAID doses given for extended periods have the same effect on presenilin 1.” Jane Bradbury How NSAIDs might prevent Alzheimer’s disease