Altered beta-adrenergic receptor-stimulated cAMP formation in cultured skin fibroblasts from Alzheimer donors.
Altered beta-adrenergic receptor-stimulated cAMP formation in cultured skin fibroblasts from Alzheimer donors.
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DOI：
10.1016/s0021-9258(18)82377-8
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发表时间：
1993-07
期刊：
影响因子：
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通讯作者：
H. M. Huang;G. Gibson
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文献类型：
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作者：
H. M. Huang;G. Gibson
阿尔茨海默病信号转导系统的改变可能具有病理生理学意义，因为这些步骤对正常的大脑功能至关重要。由于在尸检中很难研究动态过程，目前的研究使用了培养的皮肤成纤维细胞。与年龄匹配的对照组相比，阿尔茨海默病成纤维细胞中β-肾上腺素能刺激的cAMP增加减少了约80%。阿尔茨海默病成纤维细胞对各种肾上腺素能激动剂的反应缺陷与其β-肾上腺素能活性平行，非肾上腺素能激动剂如前列腺素E1对cAMP积累的促进作用在阿尔茨海默病和对照成纤维细胞中类似。腺苷环化酶活性的降低并不是这些异常的基础，因为Forsklin直接刺激腺苷环化酶同样会增加阿尔茨海默病和对照成纤维细胞中cAMP的生成。霍乱毒素同样刺激阿尔茨海默病和对照成纤维细胞中cAMP的形成。此外，霍乱毒素部分减少了异丙肾上腺素诱导的阿尔茨海默病成纤维细胞中cAMP的缺失。另一方面，百日咳毒素并没有改变阿尔茨海默氏症的缺陷。这些结果提示，阿尔茨海默病患者，要么是GTP结合蛋白(S)与β-肾上腺素能受体偶联异常，要么是受体的敏感性发生改变。此外，任何关于阿尔茨海默病的假说都必须解释为什么在组织培养中β-肾上腺素能刺激的cAMP形成减少。
An alteration in signal transduction systems in Alzheimer's disease would likely be of pathophysiological significance, because these steps are critical to normal brain function. Since dynamic processes are difficult to study in autopsied brain, the current studies utilized cultured skin fibroblasts. The beta-adrenergic-stimulated increase in cAMP was reduced approximately 80% in fibroblasts from Alzheimer's disease compared with age-matched controls. The deficit in Alzheimer fibroblasts in response to various adrenergic agonists paralleled their beta-adrenergic potency, and enhancement of cAMP accumulation by a non-adrenergic agonist, such as prostaglandin E1, was similar in Alzheimer and control fibroblasts. Diminished adenylate cyclase activity did not underlie these abnormalities, since direct stimulation of adenylate cyclase by forskolin elevated cAMP production equally in Alzheimer and control fibroblasts. Cholera toxin equally stimulated cAMP formation in Alzheimer and control fibroblasts. Moreover, cholera toxin partially reduced isoproterenol-induced cAMP deficit in Alzheimer fibroblasts. Pertussis toxin, on the other hand, did not alter the Alzheimer deficits. The results suggest either that the coupling of the GTP-binding protein(s) to the beta-adrenergic receptor is abnormal or that the sensitivity of receptor is altered with Alzheimer's disease. Further, any hypothesis about Alzheimer's disease must explain why a reduced beta-adrenergic-stimulated cAMP formation persists in tissue culture.