The decrease of the Amyloid beta production by NSAID

Alzheimer`s Disease (AD) is the most common dementia in our society. Given the gradual aging of our population and the fact that aging is major risk factor for AD, development of therapeutical strategies to prevent this disorder is of high priority. Trying to decrease of the production of Amyloid beta (Abeta) has been envisaged as a promising approach to prevent AD. Epidemiological studies support the role of chronic inflammation and microglial activation in AD, showing that the use of non-steroidal anti-inflammatory drugs (NSAIDs) might delay onset and slow the progression of the disease. However, our understanding of mechanism of NSAIDs is still sparse. We recently found that inflammatory cytokines IL-1beta, TNFalpha and IFNgamma induce Abeta production. This finding offers a novel possibility regarding how inflammation may contribute to the neuropathology of AD. Based on our results showing the importance of cytokines in the stimulation of Abeta production, we want to test which NSAIDs most effectively suppress production of Abeta. Results of our work will contribute to a better understanding of the protective mechanisms of NSAIDs against AD and we hope to contribute to improved knowledge about anti-inflammatory based therapeutic approaches for the treatment of AD.

Alzheimer`s disease (AD) is the most common dementia form in our society. The age is still the most important risk factor for later development of dementia. As growing older is a typical demographically feature of our population, the nearest future will be confronted with increasing numbers of demented patients. In the developed countries AD is already 3rd most frequent cause of death in persons over 65 years. The current treatment of AD is regarded from the pathophysiological point of view symptomatically. The clinical studies with patients have demonstrated that the therapeutic treatment can only be envisaged in patients with the earliest stages of disease. Therefore, the scientific efforts of the last years aimed to the development of therapies with early therapeutic and preventive design. In the scientific field it is widely recognised that the earliest changes, which leads to development of AD, begin in the dysregulation of the production versus the degradation of Amyloid beta (Aß) peptide. Epidemiological studies in the last decade have shown that taking of non-steroidal anti- inflammatory drugs (NSAIDs) prevents the development of AD in 60% of the users. How NSAIDs inhibits the cascade of pathogenetic changes leading to AD was widely investigated, however the precise mechanisms according to the Aß-production were not addressed. The aim of this project was to investigate, how NSAIDs such us ibuprofen, indomethacin and diclofenac influence the secretion of Aß-peptides in human cells. We used neuronal cells and human astrocytes isolated post mortem from brain of AD-patients. The cells were pre-incubated with NSAIDs for 24 hours and then the Aß-production stimulating combination of inflammatory cytokines IFN plus TNFa was added to the cultures. In these experiments, the pre-incubation of cell cultures with NSAIDs induced the decreased production of cytokine stimulated Aß production. This was detected in cell culture supernatants as well as in cell extract of both cell types used. Interestingly, compared to diclofenac and indometacine, ibuprofen was the strongest inhibitor of cytokines- stimulated Aß-production. The results of this project demonstrate that certain NSAIDs are able to influence the pathogenesis of AD by direct influencing the production of Aß peptides. Because of the still important gastrointestinal toxicity of this group of drugs, they are still avoided from wide clinical use.