Greenwood A F, Powers R E, Jope R S
Department of Psychiatry and Behavioral Neurobiology, University of Alabama, Birmingham 35294-0017, USA.
Neuroscience. 1995 Nov;69(1):125-38. doi: 10.1016/0306-4522(95)00220-d.
Influences of post mortem time interval, subject age and Alzheimer's disease were investigated on several components of the phosphoinositide second messenger system, including stimulation of [3H]phosphatidylinositol hydrolysis by GTP[S] and several receptor agonists and the levels of Galphaq, beta, delta and gamma subtypes of phospholipase C, and five protein kinase C isoforms, in membranes prepared from post mortem human prefrontal cortex. Most of these components were stable with post mortem delays in the range of 5-21 h, but decreases of Galphaq and the alpha and xi protein kinase C subtypes were detected. Within the subject age range of 19-100 years, G-protein- and agonist-induced [3H]phosphatidylinositol hydrolysis decreased, as did levels of Galphaq, but the levels of phospholipase C and protein kinase C subtypes were generally unchanged. In Alzheimer's disease, compared with age- and post mortem interval-matched controls, there was a decrease in [3H]phosphatidylinositol hydrolysis stimulated by G-proteins and by several receptor agonists, but the levels of Galphaq and most of the phospholipase C and protein kinase C isoforms were unaffected. The greatest deficits, which were >50%, occurred with GTP[S]- and carbachol-induced [3H]phosphatidylinositol hydrolysis, indicating that this G-protein function and the response to cholinergic stimulation are significantly impaired in Alzheimer's disease. In summary a comprehensive assessment of several components of the phosphoinositide second messenger system was made in post mortem human brain. Most elements were stable within the post mortem interval range of 5-21 h, lending validity to measurements using these tissues. Significant age-related reductions in several components were identified, indicating loss of responses with increasing age. Most importantly, severe reductions in responses to several stimuli were found in Alzheimer's disease brain, deficits in signal transduction which may contribute to impaired cognition and to the limited therapeutic responses to drugs, such as those used to activate cholinergic receptors coupled with the phosphoinositide system.
研究了死后时间间隔、受试者年龄和阿尔茨海默病对磷酸肌醇第二信使系统几个组分的影响，这些组分包括GTP[S]和几种受体激动剂对[3H]磷脂酰肌醇水解的刺激作用，以及磷脂酶C的Gαq、β、δ和γ亚型水平，和五种蛋白激酶C亚型，实验材料为死后人类前额叶皮质制备的膜。这些组分中的大多数在死后延迟5 - 21小时范围内是稳定的，但检测到Gαq以及α和ξ蛋白激酶C亚型减少。在19 - 100岁的受试者年龄范围内，G蛋白和激动剂诱导的[3H]磷脂酰肌醇水解减少，Gαq水平也降低，但磷脂酶C和蛋白激酶C亚型的水平通常没有变化。在阿尔茨海默病中，与年龄和死后间隔匹配的对照组相比，G蛋白和几种受体激动剂刺激的[3H]磷脂酰肌醇水解减少，但Gαq以及大多数磷脂酶C和蛋白激酶C亚型的水平未受影响。最大的缺陷（超过50%）出现在GTP[S]和卡巴胆碱诱导的[3H]磷脂酰肌醇水解中，表明在阿尔茨海默病中这种G蛋白功能和对胆碱能刺激的反应明显受损。总之，对死后人类大脑中磷酸肌醇第二信使系统的几个组分进行了全面评估。大多数成分在死后间隔5 - 21小时范围内是稳定的，这使得使用这些组织进行测量具有有效性。确定了几个组分与年龄相关的显著降低，表明随着年龄增长反应能力丧失。最重要的是，在阿尔茨海默病大脑中发现对几种刺激的反应严重降低，信号转导缺陷可能导致认知受损以及对药物（如用于激活与磷酸肌醇系统偶联的胆碱能受体的药物）的治疗反应有限。
