A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity
A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity
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DOI：
10.1038/35102591
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发表时间：
2001-11-08
期刊：
影响因子：
64.8
通讯作者：
Koo, EH
中科院分区：
文献类型：
--
作者：
Weggen, S;Eriksen, JL;Koo, EH
流行病学研究表明，使用非甾体抗炎药（NSAIDs）可降低阿尔茨海默病的患病率（1-5）。有人提出，非甾体抗炎药发挥其有益作用的部分原因是减少大脑中的神经毒性炎症反应，尽管这一机制尚未得到证实。在这里，我们报道了非甾体抗炎药布洛芬、吲哚美辛和磺化舒林酸能优先降低多种培养细胞产生的高度淀粉样蛋白A β 42肽（淀粉样蛋白β肽的42-残基异构体）高达80%。这种作用并不是在所有非甾体抗炎药中都发现的，似乎也不是通过抑制环氧化酶（COX）活性介导的，COX是非甾体抗炎药的主要药理靶点(6)。此外，对产生突变β -淀粉样蛋白前体蛋白（APP）的小鼠短期服用布洛芬，降低了它们大脑中β 42的水平。在培养的细胞中，A β 42分泌的减少伴随着A β(1-38)异构体的增加，这表明非甾体抗炎药微妙地改变了γ -分泌酶的活性，而没有显著干扰其他APP加工途径或Notch切割。我们的研究结果表明，非甾体抗炎药通过降低A β 42肽水平而不依赖于COX活性，直接影响大脑淀粉样蛋白病理，并且可以优化这种降低A β 42的活性，以选择性地靶向致病性A β 42物种。
Epidemiological studies have documented a reduced prevalence of Alzheimer's disease among users of nonsteroidal anti-inflammatory drugs (NSAIDs)(1-5). It has been proposed that NSAIDs exert their beneficial effects in part by reducing neurotoxic inflammatory responses in the brain, although this mechanism has not been proved. Here we report that the NSAIDs ibuprofen, indomethacin and sulindac sulphide preferentially decrease the highly amyloidogenic A beta 42 peptide (the 42-residue isoform of the amyloid-beta peptide) produced from a variety of cultured cells by as much as 80%. This effect was not seen in all NSAIDs and seems not to be mediated by inhibition of cyclooxygenase (COX) activity, the principal pharmacological target of NSAIDs(6). Furthermore, short-term administration of ibuprofen to mice that produce mutant beta -amyloid precursor protein (APP) lowered their brain levels of A beta 42. In cultured cells, the decrease in A beta 42 secretion was accompanied by an increase in the A beta (1-38) isoform, indicating that NSAIDs subtly alter gamma -secretase activity without significantly perturbing other APP processing pathways or Notch cleavage. Our findings suggest that NSAIDs directly affect amyloid pathology in the brain by reducing A beta 42 peptide levels independently of COX activity and that this A beta 42-lowering activity could be optimized to selectively target the pathogenic A beta 42 species.