Sci. Aging Knowl. Environ., 29 September 2004
Vol. 2004, Issue 39, p. nf89
[DOI: 10.1126/sageke.2004.39.nf89]


Knife Jugglers

Painkillers shift Alzheimer's protein slicer

R. John Davenport

A small slip at the cutting board can mean the difference between beautifully diced vegetables and a severed finger. An even more subtle miss might explain how one class of painkillers reduces the risk of Alzheimer's disease (AD). According to new work, the drugs nudge a cellular butcher, prodding it to dice a protein into a harmless form rather than one that clumps in the brains of AD patients. The study reveals how the painkillers alter the protein chopper and might provide a new method for identifying potential AD drugs.

In AD, globs of {beta}-amyloid protein riddle brains, and memory fades. According to some epidemiological studies, common painkillers--nonsteroidal anti-inflammatory drugs (NSAIDs)--decrease the risk of AD (see "Detangling Alzheimer's Disease"); NSAIDs also reduce the load of {beta} amyloid in mouse brains. Several studies suggest that they do so by perturbing the enzyme that produces the brain pollutant--{gamma} secretase--rather than by foiling proteins called cyclooxygenases (COX), which the drugs harness to tame inflammation (see "More Than a Painkiller").

{gamma} secretase whittles {beta} amyloid out of a larger molecule called {beta}-amyloid precursor protein (APP). Previous studies suggested that cells treated with NSAIDs produce less A{beta} 42--a form particularly prone to clumping--and more A{beta} 38--a nonclumping variety. To investigate how, the researchers attached a fluorescent molecule near the cutting blade of presenilin 1 (PS1), a component of {gamma} secretase. Next, they glued a different fluorescent molecule to one end of APP. The second glowing molecule dampened the light emitted from the first in proportion to the distance between them, allowing the scientists to determine how close the PS1 knife and the end of APP were. When the team added the NSAID ibuprofen to cells carrying the glowing versions of APP and PS1, fluorescence dimmed more slowly than it did in untreated cells, suggesting that ibuprofen shifts the position of APP on PS1's cutting surface. NSAID-related molecules that do not inhibit COX also kept the light burning, suggesting that the drugs act directly on {gamma} secretase rather than through COX.

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Switch blade. Presenilin 1 (PS1) grips {beta}-amyloid precursor protein differently when treated with NSAIDs (left) than when untreated (right). As a result, NSAIDs quell production of A{beta} 42, the form that clumps in Alzheimer's disease, and favor generation of A{beta} 38, which doesn't clump.

Next, the team attached the two fluorescent molecules to either end of PS1. In the presence of NSAIDs, the compounds moved apart. Chemicals that slow cutting by {gamma} secretase did not change the fluorescence pattern. These observations suggest that NSAIDs alter the shape of PS1 rather than dull its blades.

"They've applied a really cool optical technique to a problem that previously had not been approached this way," says neuroscientist Gary Landreth of Case Western Reserve University in Cleveland, Ohio. "They've shown unequivocally that [NSAIDs] change the conformation both of PS1 in relation to itself and to its substrate." Neurologist Giulio Pasinetti of Mount Sinai School of Medicine in New York City notes that this study and previous work delving into NSAIDs' effect on {gamma} secretase use much higher concentrations than those that patients typically receive. "It may not be clinically relevant," he says, but the technique could prove useful in testing for stronger compounds that alter the shape of {gamma} secretase. That effort might reveal ways to keep AD from cutting into people's lives.

September 29, 2004

Suggested by Amir Sadighi Akha.

  1. A. Lleó et al., Nonsteroidal anti-inflammatory drugs lower A{beta} 42 and change presenilin 1 conformation. Nat. Med., 26 September 2004 [e-pub ahead of print]. [Abstract/Full Text]
Citation: R. J. Davenport, Knife Jugglers. Sci. Aging Knowl. Environ. 2004 (39), nf89 (2004).

Science of Aging Knowledge Environment. ISSN 1539-6150