title: Non-steroidal anti-inflammatory drugs mediate increased in vitro glial expression of apolipoprotein E protein.
abstract: Epidemiological studies have shown that use of non-steroidal anti-inflammatory drugs (NSAIDs) by the elderly is associated with a decreased relative risk and a delayed onset of Alzheimer's disease (AD). In contrast, the apolipoprotein E (apoE) gene has proven to be a risk factor for AD with apoE epsilon 4 AD patients having been found to show lower levels of brain apoE. In the present study, treatment of primary rat mixed glial cell cultures with the common NSAIDs, indomethacin and aspirin, induced significant increases in extracellular apoE protein levels. Similarly, treatment of primary rat astrocyte cell cultures with aspirin and a cyclooxygenase (COX)-2-selective aspirin derivative also stimulated significant increases in apoE protein. However, astrocyte and mixed glial apoE protein levels were significantly reduced following exposure to COX-2-specific indomethacin amides and an inactive indomethacin derivative. ApoE protein modulation was observed at physiological and subphysiological concentrations well below the COX inhibition IC50 values of the NSAIDs used, suggestive of a COX-independent mechanism. In contrast to these results, indomethacin and aspirin treatment failed to induce any significant changes in apoE mRNA levels. The failure of NSAIDs to significantly alter apoE expression may have been indicative of a nontranscriptional mechanism of apoE protein induction. Consequently, NSAID-induced increases in apoE protein may enhance apoE-mediated immunosuppression and compensatory synaptic plasticity, potentially resulting in decreased AD risk and delay of disease onset.
mesh_terms: D000165:Acridine Orange / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D053331:Ectodysplasins; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005110:Extracellular Space / Q000378:metabolism; D005699:Galactosylceramides / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008565:Membrane Proteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000295:instrumentation / Q000379:methods; D013997:Time Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001057:Apolipoproteins E; D053331:Ectodysplasins; D005699:Galactosylceramides; D005904:Glial Fibrillary Acidic Protein; D008565:Membrane Proteins; D012333:RNA, Messenger; C002454:galactocerebroside; D000165:Acridine Orange