More Than a Painkiller: Ibuprofen's hidden talent thwarts Alzheimer's disease

R. John Davenport

Key Words: NSAID • ibuprofen • Alzheimer's disease • -secretase • APP • presenilin

Abstract: As the Mona Lisa smiled from the wall, her creator scribbled down ideas for his flying machine. Sometimes a superstar's famous gifts overshadow additional genius. That appears to be the case for a drug that might prevent Alzheimer's disease (AD): According to new work, ibuprofen blocks the formation of brain-gumming amyloid plaques (see "Detangling Alzheimer's Disease" ) by a mechanism unrelated to its starring role as an anti-inflammatory painkiller.

Several epidemiological studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) protect people from AD. Recent experiments showed that the NSAID ibuprofen reduces the number of brain plaques in a mouse model of AD when administered in high doses. Because chronic inflammation in the Alzheimer's brain releases neurotoxins and molecules that promote plaque formation, scientists ascribed the effect of NSAIDs to the anti-inflammatory power of the drugs. The new results suggest an alternative mechanism for NSAIDs' AD-fighting power: They directly block the generation of a protein that clumps into plaques in the brain. The results might explain the mixed outcomes of recent NSAID clinical trials for AD and could help drugmakers circumvent the potential side effects of compounds currently in development.

In a key event during the development of AD, an enzyme activity known as -secretase trims the so-called -amyloid precursor protein (APP) into a sticky, plaque-forming protein called A 42. Weggen and colleagues tested whether various NSAIDs influence this molecular snipping. The researchers engineered cultured hamster cells to produce large amounts of both APP and a deviant version of a protein called presenilin 1 (PS1), which might be -secretase itself and in any case is required for -secretase function. When the cells were exposed to either of three NSAIDs--ibuprofen, indomethacin, or sulindac sulfide--the ratio of A 42 to the shorter, more benign A 40 fell as compared with untreated cells. Results from live animals further suggest that ibuprofen dulls the scissors that shape A 42: In mice engineered to produce large amounts of an AD-associated form of APP, those that were treated with ibuprofen carried 40% less A 42 than untreated ones did.

NSAIDs reduce inflammation primarily by inhibiting cyclooxygenase (COX) enzymes, which rev up production of inflammatory prostaglandins. To find out whether NSAIDs depend on COX inhibition to deflate A 42 production, the researchers engineered COX-1- and COX-2-deficient mouse cells to manufacture large amounts of normal APP. Sulindac sulfide treatment reduced A 42 levels, even in the absence of COX. Together, the results indicate that certain NSAIDs can hinder a crucial biochemical step in the genesis of AD--A 42 formation--a capability distinct from their usual anti-inflammatory action.

Other NSAIDs, however--including naproxen, aspirin, and celecoxib--do not reduce the amount of A 42 in cells that overproduce APP. These combined observations could explain the mixed results of clinical trials with NSAIDs: Some of these drugs have shown promise in preventing AD, whereas others have not.

Many drugs currently in development inhibit beneficial activities of -secretase, which leads to faulty T cell development. Additional work in the current study suggests that sulindac-sulfide-treated cells do not suffer from the molecular deviations that underlie these side effects. The new work hints that drugs based on the structure of, for instance, ibuprofen might inhibit the production of A 42 but leave the normal functions of -secretase intact. Such an agent could transform this obscure forte of ibuprofen into a celebrated talent.

--R. John Davenport

S. Weggen, J. L. Eriksen, P. Das, S. A. Sagi, R. Wang, C. U. Pietrzik, K. A. Findlay, T. E. Smith, M. P. Murphy, T. Butler, D. E. Kang, N. Marquez-Sterling, T. E. Golde, E. H. Koo, A subset of NSAIDs lower amyloidogenic A42 independently of cyclooxygenase activity. Nature 414, 212-216 (2001).

[Abstract] [Full Text]

Citation: R. J. Davenport, More Than a Painkiller: Ibuprofen's hidden talent thwarts Alzheimer's disease. Science's SAGE KE (7 November 2001), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2001/6/nw23