If anti-inflammatory drugs are, in fact, helping some patients counteract the neurodegeneration of Alzheimer's disease, the benefit may not come from the most obvious effects of those drugs. Eddie Koo and Sascha Weggen of the University of California, San Diego, with colleagues at a number of other institutions, report in today's issue of Nature that a subset of nonsteroidal anti-inflammatory drugs (NSAIDs) lower toxic amyloidβ (Aβ) levels independent of effects on inflammatory processes.

A number of factors have pointed to inflammatory processes in Alzheimer's disease, including elevated levels of inflammatory molecules and the presence of astrocytes and microglia surrounding amyloid plaques. In addition, epidemiological studies have hinted that regular use of NSAIDs reduces the risk of AD. The assumption has been that it was the direct anti-inflammatory action of NSAIDs, principally against cyclooxygenase (COX) activity, that conferred this benefit.

Koo and colleagues looked in another direction, at the effects of NSAIDs on the Aβ42 peptide, which is widely considered the culprit in AD. They found that the NSAIDs ibuprofen, indomethacin, and sulindac sulphide decrease, by as much as 80 percent, the amount of Aβ42 secreted from a variety of cultured cells. In contrast, other NSAIDs (e.g., sulindac sulphone, naproxen) did not reduce Aβ42 levels. Because naproxen is a COX inhibitor, the results suggested that COX inhibition is not essential to the reduction of Aβ42. Evidence supporting this hypothesis came from an experiment in which sulindac sulphide successfully reduced Aβ42 in cells deficient in COX enzymes. Extending their work to the Tg2576 mouse model of AD, which produces mutant human β-amyloid precursor protein, the researchers found that ibuprofen, but not naproxen, significantly reduced levels of Aβ42 (but not of the less toxic Aβ40).

A second focus of this study was to examine how NSAIDs affect the mechanism whereby the AβPP protein is cleaved to produce either the Aβ42 peptide or other, less toxic, forms. Recent efforts to inhibit Aβ42 production by targeting the γ-secretase enzyme have run into the problem that γ -secretase inhibition also interferes with normal physiological processes, in particular proteolysis of the Notch receptor. Koo et al. discovered that sulindac sulphide did not interfere with notch processing. They also found that NSAID treatment apparently lowered Aβ42 production by raising the levels of the shorter peptide Aβ38.

In an accompanying News and Views article, Bart de Strooper of the Flanders Interuniversity in Belgium and Gerhard Konig of Bayer AG in Wuppertal, Germany, issue one word of caution, pointing out that we don't know for certain that the Aβ38 peptide is harmless. However, they also praise the study results, saying, "It is surely no coincidence that positive clinical effects were seem mainly with those NSAIDs that are now known to block Aβ42 production."

For their part, the researchers anticipate the development of "'antiamyloid' drugs that selectively target production of the highly amyloidogenic Aβ42 species without inhibiting either COX activity or the vital physiological functions of γ-secretase."—Hakon Heimer


  1. This study suggests a novel mechanism by which NSAIDs might be protective in AD, and a potentially novel and selective mechanism for lowering Ab42 production. This is important because Ab42 is thought to be a critical factor initiating Ab aggregation. -- Benjamin Wolozin

    View all comments by Benjamin Wolozin
  2. The most innovative paper from 2001, which provided a novel means of
    modulating γ-secretase activity.

    View all comments by Dominic Walsh

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Primary Papers

  1. . A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature. 2001 Nov 8;414(6860):212-6. PubMed.
  2. . An inflammatory drug prospect. Nature. 2001 Nov 8;414(6860):159-60. PubMed.