Modulation of β-amyloid metabolism by non-steroidal anti-inflammatory drugs in neuronal cell cultures
Modulation of β-amyloid metabolism by non-steroidal anti-inflammatory drugs in neuronal cell cultures
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DOI：
10.1046/j.1471-4159.2003.02154.x
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发表时间：
2004-01-01
影响因子：
4.7
通讯作者：
Ongini, E
中科院分区：
文献类型：
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作者：
Gasparini, L;Rusconi, L;Ongini, E
阿尔茨海默病（AD）的特征在于β-淀粉样蛋白（Abeta）肽的脑沉积，其被神经炎性细胞包围。流行病学研究表明，长期使用非甾体抗炎药（NSAID）可降低AD的发病风险。此外，生物学数据表明，某些NSAID特异性地降低外周细胞培养物中的A β 42水平，而与环氧合酶（考克斯）活性无关，并降低AD转基因小鼠中的脑A β水平。其他NSAID，包括COX-选择性化合物，是否调节神经元细胞中的Abeta水平仍未开发。在这里，我们使用Neuro-2a细胞和大鼠原代皮层神经元研究了来自每种化学类别的NSAID的化合物对A β 40和A β 42分泌的影响。在非选择性NSAID中，氟比洛芬和舒林酸硫化物浓度依赖性地不仅减少了A β 42的分泌，还减少了A β 40的分泌。令人惊讶的是，考克斯-2（塞来昔布; sc-125）或考克斯-1（sc-560）选择性化合物均显著增加A β 42分泌，并且不改变（sc-560; sc-125）或降低（塞来昔布）A β 40水平。任何NSAID均未改变β APP C-末端片段和Notch切割的水平，表明这些药物总体上未改变γ-分泌酶活性。目前的研究结果表明，只有少数非选择性NSAID具有降低A β的特性，因此具有与其在AD中的临床应用潜在相关的特征。
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.