| MECHANISM OF ACTION |
One class of medication that may reduce one's risk of getting Alzheimer's disease is familiar to anyone who takes drugs such as ibuprofen (Advil, for example). Unfortunately, some of these nonsteroidal anti-inflammatory drugs (NSAIDs), which are currently marketed as pain relievers, have recently come under suspicion of causing cardiovascular problems (C&EN, Jan. 3, page 7). The emergence of these possible side effects has brought clinical trials of NSAIDs as a potential Alzheimer's treatment to a halt. Nevertheless, valuable information can still be garnered from studies of the drugs. NSAIDs may exert their beneficial effect against Alzheimer's by influencing the cleavage of amyloid precursor protein. APP is a large molecule of unknown function that pokes through the membrane of nerve cells. The molecule is metabolized by -, -, and -secretase enzymes. Depending on the secretases involved and the location of the cuts that they make in APP, cleavage of the molecule can produce either harmless fragments or amyloid-42 (A42) peptides that clump together into the insoluble toxic aggregates associated with Alzheimer's. Researchers are developing a variety of possible explanations for how certain NSAIDs increase the likelihood that APP is cleaved at the more favorable location. For instance, these drugs may reshape the protein site at which cleavage occurs, according to Bradley T. Hyman and colleagues in the Alzheimer's Research Unit at Massachusetts General Hospital, Charlestown [Nat. Med., 10, 1065 (2004)]. First, Hyman's team studied the effect of NSAIDs on the interaction between -secretase and APP in cell culture. The researchers showed that NSAIDs reduce the production of A42 relative to nontoxic amyloid- molecules but don't reduce the overall quantity of amyloid- molecules. "We interpret these data to suggest that NSAIDs alter APP--secretase interactions to change the site of the APP cleavage, rather than to change whether cleavage occurs," the researchers explain. "We reasoned that an alteration in the configuration of the APP--secretase interaction might lead to the observed outcome." The researchers next surveyed the geography of -secretase's cleavage site. -Secretase is an enzyme complex that includes a section known as presenilin 1 (PS1), which is thought to be the actual cleavage site. Using an assay based on fluorescence resonance energy transfer, Hyman and his colleagues showed that NSAIDs including ibuprofen and flurbiprofen open up the PS1 site and alter the relative positions of APP and PS1. "This change in the conformation of PS1 shifts the cleavage of APP toward shorter species such as A38," they note. Hyman's model is supported by results with aspirin and naproxen. These two NSAIDs--which have no effect on the relative amount of A42 generation--leave APP-PS1 positioning unchanged. |
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