Prasad K N, Hovland A R, La Rosa F G, Hovland P G
Center for Vitamins and Cancer Research, Department of Radiology, University of Colorado Health Sciences Center, School of Medicine, Denver 80262-0228, USA.
Proc Soc Exp Biol Med. 1998 Nov;219(2):120-5. doi: 10.3181/00379727-219-44323.
Chronic inflammatory reactions in the brain appear to be one of the primary etiological factors in the pathogenesis of Alzheimer's disease (AD). This is supported by the fact that the secretory products of inflammatory reactions, which include cytokines, complement proteins, adhesion molecules, and free radicals, are neurotoxic. We have recently reported that prostaglandins (PGs), which are also released during inflammatory reactions, cause rapid degenerative changes in differentiated murine neuroblastoma cells (NB) in culture. PGA1 is more effective than PGE1. Similar observations were made in a primary culture of fetal rat hippocampal cells. Epidemiological and clinical studies on AD also support the involvement of PGs in neuronal degeneration. Thus, we propose a hypothesis that PGs are one of the major extracellular signals that initiate neuronal degeneration, which is mediated by intracellular signals such as the beta-amyloid peptide (Abeta) and ubiquitin, since the levels of these proteins are increased by PG treatment. We further suggest that adenosine 3', 5'-cyclic monophosphate (cAMP) is one of the factors that regulate the levels of both Abeta and ubiquitin in NB cells. Increases in the level of Abeta in NB cells following an elevation of intracellular cAMP levels appear to be due to an increase in the rate of processing of the amyloid precursor protein (APP) rather than an increase in the expression of APP. The mechanisms underlying Abeta-induced neuronal degeneration have been under intense investigation, and several mechanisms of action have been proposed. We postulate that PG-induced elevation of Abeta may lead to an increased binding of Abeta to the 20S proteasome, resulting in a reduction of 20S proteasome-mediated degradation of ubiquitin-conjugated proteins. This is predicted to lead to an increase in an accumulation of abnormal proteins, which ultimately contribute to neuronal degeneration and death. Based on our hypothesis and on studies published by others, we propose that a combination of nonsteroidal anti-inflammatory drugs, which inhibit the synthesis of PGs, and antioxidant vitamins, which quench free radicals and both of which have been recently reported to be of some value in AD treatment when used-individually, may be much more effective in the prevention and treatment of AD than the individual agents alone.
大脑中的慢性炎症反应似乎是阿尔茨海默病（AD）发病机制中的主要病因之一。炎症反应的分泌产物，包括细胞因子、补体蛋白、黏附分子和自由基，具有神经毒性，这一事实支持了上述观点。我们最近报道，炎症反应过程中释放的前列腺素（PGs）可导致培养的分化小鼠神经母细胞瘤细胞（NB）迅速发生退行性变化。PGA1比PGE1更有效。在胎鼠海马细胞原代培养中也有类似观察结果。关于AD的流行病学和临床研究也支持PGs参与神经元变性。因此，我们提出一个假说，即PGs是引发神经元变性的主要细胞外信号之一，这种变性由细胞内信号如β-淀粉样肽（Aβ）和泛素介导，因为PG处理会使这些蛋白质的水平升高。我们进一步认为，腺苷3'，5'-环磷酸（cAMP）是调节NB细胞中Aβ和泛素水平的因素之一。细胞内cAMP水平升高后，NB细胞中Aβ水平的增加似乎是由于淀粉样前体蛋白（APP）加工速率的增加，而不是APP表达的增加。Aβ诱导神经元变性的机制一直是深入研究的对象，并且已经提出了几种作用机制。我们推测，PG诱导的Aβ升高可能导致Aβ与20S蛋白酶体的结合增加，从而导致20S蛋白酶体介导的泛素结合蛋白降解减少。预计这将导致异常蛋白质积累增加，最终导致神经元变性和死亡。基于我们的假说以及其他人发表的研究，我们提出，抑制PG合成的非甾体抗炎药与清除自由基的抗氧化维生素联合使用，最近有报道称单独使用这两种药物在AD治疗中都有一定价值，它们联合使用在AD的预防和治疗中可能比单独使用单一药物更有效。
