Can Nsaids Contribute to Alzheimer's Disease?

SCIENCE AND MEDICINE A NALYSIS Can NSAIDs contribute to Alzheimer’s disease?

everal years ago it was dis- inhibitors were coming under S covered that some NSAIDs fire for increasing the risk of ad- lower the levels of amyloid β verse cardiovascular events.3 peptide (Aβ). This peptide is a key component of neuritic plaques, which, along with neu- Mimicking Alzheimer’s disease rofibrillary tangles and cerebral In a recent study, Kukar and atrophy, are a pathologic hall- colleagues tested over 300 mark of Alzheimer’s disease. compounds, including COX-2 Not all NSAIDs produce this selective NSAIDs, NSAID de- result, however, and new re- rivatives and several novel com- search reveals that some cy- pounds, with the goal of finding clooxygenase-2 (COX-2) in- drugs that had little effect on cy- hibitors actually increase the clooxygenase but decreased the production of Aβ, an effect production of Aβ42.1 They ex- comparable to that of muta- posed cultured H4 neuroglioma tions thought to cause Alzhei- cells to various drugs and mea- 1 mer’s disease. sured production of Aβ. Photo.com There are several forms of Their results were surprising. Aβ; the one with 42 amino acids Although they discovered that used in the study have the same (Aβ42) is the insoluble form one NSAID, R-flurbiprofen, effects in the human brain as found in neuritic plaques. The lacked cyclooxygenase activity they did in the mouse model deposition of Aβ42 is thought to and reduced Aβ42 levels, many used in the study. If they do, it is play an important role in the of the COX-2 inhibitors, in- conceivable that they may have cascade of events leading to the cluding tilmacoxib and valde- an impact on the pathology of formation of neurofibrillary tan- coxib, increased the production Alzheimer’s disease, which gles and the eventual degenera- of Aβ42. In particular, celecoxib raises several issues for future tion of neurons. The production raised Aβ42 levels by almost study. The in vivo effects of of Aβ42 is catalyzed by β- and γ- 200%. Rofecoxib and lumira- COX-2 inhibitors on Aβ42 lev- secretases. In 2001, Weggen coxib only slightly influenced els and subsequent neuritic and colleagues found that the Aβ42 levels, even at high doses. plaque formation need to be as- NSAIDs ibuprofen, indometha- The COX-2 selective NSAIDs certained. An understanding of cin and sulindac sulfide decrease appeared to exert their effects how these NSAIDs modulate the levels of Aβ42 in cells, in on Aβ42 production by target- the activity of γ-secretase may some cases by as much as 80%.2 ing γ-secretase. This is similar to one day contribute to the design This decrease appears not to be the mechanism by which auto- of drugs that inhibit the produc- due to an effect on cyclooxy- somal dominant mutations tion of Aβ.3 Finally, whether the genase, the primary target of linked to Alzheimer’s disease are drug-induced alteration of Aβ42 NSAIDs. Instead, these drugs known to function. levels is a new risk factor for appear to modulate the ability of NSAIDs are not the only class Alzheimer’s disease needs fur- γ-secretase to produce Aβ42. of drug that affects Aβ42 produc- ther research. — David Secko, The results of a number of tion. Fenofibrate, a lipid-lower- Vancouver epidemiological studies that ing drug, increased the Aβ42 preceded the study by Weggen levels in cultured H4 cells by and colleagues suggested that over 300% in a dose-dependent References 1. Kukar T, Murphy MP, Eriksen JL, people using NSAIDs had a re- fashion. In contrast, fenofibric Sagi SA, Weggen S, Smith TE, et al. duced incidence of Alzheimer’s acid, the active metabolite of Diverse compounds mimic Alzheimer disease. This led to speculation fenofibrate, did not raise Aβ42 disease-causing mutations by aug- menting Abeta42 production. Nat that NSAIDs may aid in pre- levels, which suggests that the ef- Med 2005;11(6):545-50. venting this disease. However, fect was specific to the drug. 2. Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, et al. A clinical trials with rofecoxib and The clinical implications of subset of NSAIDs lower amyloido- naproxen showed no benefit. A these findings are not clear, as genic Abeta42 independently of cy- prevention trial for Alzheimer’s the authors point out.1 In partic- clooxygenase activity. Nature 2001; 414(6860):212-6. disease using celecoxib was re- ular, it is uncertain whether 3. Wyss-Coray T. Killing pain, killing

DOI:10.1503/cmaj.050601 cently halted because COX-2 celecoxib and the other drugs neurons? Nat Med 2005;11(5):472-3.

CMAJ • JUNE 21, 2005; 172 (13) 1677