New research at the University of California, San Diego (UCSD) and the Mayo Clinic, Jacksonville, Fla, shows nonsteroidal anti-inflammatory drugs (NSAIDs) use a novel mechanism to decrease the harmful amyloid-beta 42 protein (AB42) that forms brain plaques in Alzheimer’s disease patients.
According to the study published in the Nov. 8, 2001 issue of the journal Nature, findings suggest that NSAID therapy has a direct impact on the cause of Alzheimer’s disease, which is believed to be the abnormal deposition of AB42 in the brain. This medication offers hope for the development of highly effective plaque-reducing drugs, without the toxic side effects associated with anti-inflammatory medications.
NSAIDs are known to inhibit master enzymes called cyclooxygenases (COX), which control inflammatory responses. It therefore has been assumed by many researchers that NSAIDs are effective in Alzheimer’s disease because they reduce the toxic, inflammatory process in the brain. Although some individuals who chronically take NSAIDs have shown reduced risk of developing Alzheimer’s disease, the exact mechanism of action of these drugs remains unclear.
The new study is the first to demonstrate a specific pharmacological inhibition of AB42 production. Specifically, the NSAIDs ibuprofen, indomethacin and sulindac sulphide decreased AB42 by as much as 80 percent. However, the results don’t mean that physicians should begin to prescribe these three drugs for Alzheimer’s patients.
“The dose required to inhibit production of AB42 is far too high. This is a secondary effect of the NSAIDs. For example, a patient would need to take the equivalent of more than 16 tablets of Advil a day,” said Edward Koo, M.D., UCSD Department of Neurosciences. “Instead, our findings suggest a new mechanism through which NSAIDs might confer protection from Alzheimer’s disease – a mechanism independent of direct anti-inflammatory properties of NSAIDs. ”
Since not all NSAIDs are the same, the research team conducted their studies by treating rodent and human cells in laboratory culture dishes with various NSAIDs, then analyzing AB42 levels. While the NSAIDs ibuprofen, indomethacin and sulindac sulphide lowered AB42, other NSAIDs, including aspirin, Naproxen and celecoxib, had no effect on AB42. Similar results were found in studies with mice.
Koo noted that since many researchers and clinicians have proposed that NSAIDs are effective treatments for Alzheimer’s disease because they inhibit COX enzymes and therefore inflammation, the UCSD/Mayo team decided to test a new theory. They took cells genetically engineered to lack the COX enzymes and treated them with sulindac. The results showed the reduction of AB42 levels, indicating that a decrease of AB42 levels is completely independent of COX activity.
“These results provide compelling evidence that the reduction in AB42 is not mediated by inhibition of COX activity, the principle mode of action of NSAIDs,” the authors stated in the Nature paper.