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Modulation of β‐amyloid metabolism by non‐steroidal anti‐inflammatory drugs in neuronal cell cultures
Author(s) -
Gasparini Laura,
Rusconi Laura,
Xu Huaxi,
Del Soldato Piero,
Ongini Ennio
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02154.x
Subject(s) - celecoxib , cyclooxygenase , secretion , pharmacology , flurbiprofen , chemistry , microglia , amyloid precursor protein , intracellular , genetically modified mouse , alzheimer's disease , medicine , inflammation , biochemistry , disease , transgene , enzyme , gene
Alzheimer disease (AD) is characterized by cerebral deposits of β‐amyloid (Aβ) 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 Aβ42 levels in cultures of peripheral cells independently of cyclooxygenase (COX) activity and reduce cerebral Aβ levels in AD transgenic mice. Whether other NSAIDs, including COX‐selective compounds, modulate Aβ levels in neuronal cells remains unexploited. Here, we investigated the effects of compounds from every chemical class of NSAIDs on Aβ40 and Aβ42 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 Aβ42 but also of Aβ40. Surprisingly, both COX‐2 (celecoxib; sc‐125) or COX‐1 (sc‐560) selective compounds significantly increased Aβ42 secretion, and either did not alter (sc‐560; sc‐125) or reduced (celecoxib) Aβ40 levels. The levels of βAPP C‐terminal fragments and Notch cleavage were not altered by any of the NSAIDs, indicating that γ‐secretase activity was not overall changed by these drugs. The present findings show that only a few non‐selective NSAIDs possess Aβ‐lowering properties and therefore have a profile potentially relevant to their clinical use in AD.