Lee R K, Knapp S, Wurtman R J
Division of Health Sciences and Technology, Massachusetts Institute of Technology-Harvard University, Cambridge, Massachusetts 02139, USA.
J Neurosci. 1999 Feb 1;19(3):940-7. doi: 10.1523/JNEUROSCI.19-03-00940.1999.
Amyloid plaques that accumulate in the brains of patients with Alzheimer's disease (AD) are primarily composed of aggregates of amyloid peptides that are derived from the amyloid precursor protein (APP). Overexpression of APP in cell cultures increases the formation of amyloidogenic peptides and causes neurodegeneration and cognitive dysfunction in transgenic mice. We now report that activation of prostaglandin E2 (PGE2) receptors increases cAMP formation and stimulates overexpression of APP mRNA and holoprotein in primary cultures of cortical astrocytes. Levels of glial fibrillary acidic protein were also increased by PGE2 treatment, suggesting that these cultured astrocytes resemble reactive astrocytes found in vivo. The stimulation by PGE2 of APP synthesis was mimicked or blocked by activators or inhibitors, respectively, of protein kinase A. Actinomycin D or cycloheximide also inhibited the increase in APP holoprotein stimulated by PGE2. Treatment of astrocytes with 8-Bromo-cAMP or forskolin for 24 hr also stimulated APP overexpression in cultured astrocytes. The immunosuppressants cyclosporin A and FK-506 inhibited the increase in APP mRNA and holoprotein levels caused by PGE2 or by other treatments that elevated cellular cAMP levels; the inhibitory effect of FK-506 but not of cyclosporin A was attenuated by rapamycin. These results suggest that prostaglandins produced by brain injury or inflammation can activate APP transcription in astrocytes and that immunosuppressants may be used to prevent APP overexpression and possibly the pathophysiological processes underlying AD.
在阿尔茨海默病（AD）患者大脑中积累的淀粉样斑块主要由源自淀粉样前体蛋白（APP）的淀粉样肽聚集体组成。在细胞培养中APP的过表达会增加淀粉样生成肽的形成，并在转基因小鼠中导致神经退行性变和认知功能障碍。我们现在报告，前列腺素E2（PGE2）受体的激活会增加cAMP的形成，并刺激皮质星形胶质细胞原代培养物中APP mRNA和全蛋白的过表达。PGE2处理也会增加胶质纤维酸性蛋白的水平，这表明这些培养的星形胶质细胞类似于体内发现的反应性星形胶质细胞。PGE2对APP合成的刺激分别被蛋白激酶A的激活剂或抑制剂模拟或阻断。放线菌素D或环己酰亚胺也抑制了PGE2刺激的APP全蛋白增加。用8-溴-cAMP或福斯高林处理星形胶质细胞24小时也会刺激培养的星形胶质细胞中APP的过表达。免疫抑制剂环孢素A和FK-506抑制了PGE2或其他提高细胞cAMP水平的处理所导致的APP mRNA和全蛋白水平的增加；雷帕霉素减弱了FK-506而非环孢素A的抑制作用。这些结果表明，脑损伤或炎症产生的前列腺素可激活星形胶质细胞中的APP转录，免疫抑制剂可能用于预防APP的过表达以及可能预防AD潜在的病理生理过程。
