Can NSAIDs contribute to Alzheimer's disease?(Science and Medicine)

Several years ago it was discovered that some NSAIDs lower the levels of amyloid a peptide (Aa). This peptide is a key component of neuritic plaques, which, along with neurofibrillary tangles and cerebral atrophy, are a pathologic hallmark of Alzheimer's disease. Not all NSAIDs produce this result, however, and new research reveals that some cyclooxygenase-2 (COX-2) inhibitors actually increase the production of Aa, an effect comparable to that of mutations thought to cause Alzheimer's disease. (1)

There are several forms of A[beta]; the one with 42 amino acids (A[beta]42) is the insoluble form found in neuritic plaques. The deposition of A[beta]42 is thought to play an important role in the cascade of events leading to the formation of neurofibrillary tangles and the eventual degeneration of neurons. The production of A[beta]42 is catalyzed by [beta]- and [gamma]- secretases. In 2001, Weggen and colleagues found that the NSAIDs ibuprofen, indomethacin and sulindac sulfide decrease the levels of A[beta]42 in cells, in some cases by as much as 80%. (2) This decrease appears not to be due to an effect on cyclooxygenase, the primary target of NSAIDs. Instead, these drugs appear to modulate the ability of [gamma]-secretase to produce Abeta]42.

The results of a number of epidemiological studies that preceded the study by Weggen and colleagues suggested that people using NSAIDs had a reduced incidence of Alzheimer's disease. This led to speculation that NSAIDs may aid in preventing this disease. However, clinical trials with rofecoxib and naproxen showed no benefit. A prevention trial for Alzheimer's disease using celecoxib was recently halted because COX-2 inhibitors were coming under fire for increasing the risk of adverse cardiovascular events. (3)

Mimicking Alzheimer's disease

In a recent study, Kukar and colleagues tested over 300 compounds, including COX-2 selective NSAIDs, NSAID derivatives and several novel compounds, with the goal of finding drugs that had little effect on cyclooxygenase but decreased the production of A[beta]42. (1) They exposed cultured H4 neuroglioma cells to various drugs and measured production of A[beta].

Their results were surprising. Although they discovered that one NSAID, R-flurbiprofen, lacked cyclooxygenase activity and reduced A[beta]42 levels, many of the COX-2 inhibitors, including tilmacoxib and valdecoxib, ...