Modulation of beta-amyloid metabolism by non-steroidal anti-inflammatory drugs in neuronal cell cultures.
Alzheimer disease (AD) is characterized by cerebral deposits of beta-amyloid (Abeta) peptides, which are surrounded by neuroinflammatory cells. Epidemiological studies have shown that prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD. In addition, biological data indicate that certain NSAIDs specifically lower Abeta42 levels in cultures of peripheral cells independently of cyclooxygenase (COX) activity and reduce cerebral Abeta levels in AD transgenic mice. Whether other NSAIDs, including COX-selective compounds, modulate Abeta levels in neuronal cells remains unexploited. Here, we investigated the effects of compounds from every chemical class of NSAIDs on Abeta40 and Abeta42 secretion using both Neuro-2a cells and rat primary cortical neurons. Among non-selective NSAIDs, flurbiprofen and sulindac sulfide concentration-dependently reduced the secretion not only of Abeta42 but also of Abeta40. Surprisingly, both COX-2 (celecoxib; sc-125) or COX-1 (sc-560) selective compounds significantly increased Abeta42 secretion, and either did not alter (sc-560; sc-125) or reduced (celecoxib) Abeta40 levels. The levels of betaAPP C-terminal fragments and Notch cleavage were not altered by any of the NSAIDs, indicating that gamma-secretase activity was not overall changed by these drugs. The present findings show that only a few non-selective NSAIDs possess Abeta-lowering properties and therefore have a profile potentially relevant to their clinical use in AD.
Gasparini
Laura
L
Nicox Research Institute, Bresso, Milan, Italy. gasparini@nicox.it
Rusconi
Laura
L
Xu
Huaxi
H
del Soldato
Piero
P
Ongini
Ennio
E
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar
D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)