Holmes T C, Nitsch R M, Erfurth A, Wurtman R J
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge 02139.
Ann N Y Acad Sci. 1993 Sep 24;695:241-3. doi: 10.1111/j.1749-6632.1993.tb23060.x.
Membrane phospholipid metabolism is abnormal in Alzheimer's disease (AD) brain. Phosphatidylcholine and phosphatidylethanolamine levels are decreased as are choline and ethanolamine, while glycerophosphocholine (GPC) and glycerophosphoethanolamine are increased. To develop a rat model for these changes, we examined the effects of unilateral lesion of the cholinergic nucleus basalis (nBM) with ibotenic acid (10 mg/ml in PBS, 0.5 microliter) and sham lesion on frontocortical phospholipid, choline and GPC. After one week, choline acetyltransferase activity in frontal cortex was decreased (26%, p < 0.005, n = 14) on the nBM ibotenate-lesion side relative to the contralateral side, while there were no differences following the nBM sham-lesion. Levels of membrane phospholipids (nmol/mg protein) in adjacent frontal cortex sections exhibited concomitant decreases (13%, p < 0.05, n = 14) on the nBM ibotenate-lesion side, while there were no differences following the nBM sham-lesion. Tissue nBM ibotenate-lesion frontocortical choline and GPC levels were also decreased relative to those in control tissue (choline: 21%, p < 0.05, n = 14; GPC: 10%, p < 0.05, n = 14), while nBM sham-lesion showed no effect. Muscarinic receptor sensitivity in frontal cortex following nBM ibotenate-lesion was increased, as measured by carbachol-stimulated inositol phosphate production (p < 0.001, n = 12), indicating that increased receptor mediated phospholipid hydrolysis in cortex may occur following nBM ibotenate-lesion. These data suggest that impaired cholinergic transmission alters phospholipid metabolism in cholinergic target regions.
阿尔茨海默病（AD）患者大脑中的膜磷脂代谢异常。磷脂酰胆碱和磷脂酰乙醇胺水平降低，胆碱和乙醇胺水平也降低，而甘油磷酸胆碱（GPC）和甘油磷酸乙醇胺则升高。为了建立反映这些变化的大鼠模型，我们研究了用异博定酸（10 mg/ml溶于PBS，0.5微升）单侧损伤胆碱能基底核（nBM）以及假损伤对额叶皮质磷脂、胆碱和GPC的影响。一周后，相对于对侧，nBM异博定酸损伤侧额叶皮质中的胆碱乙酰转移酶活性降低（26%，p < 0.005，n = 14），而nBM假损伤后则无差异。相邻额叶皮质切片中的膜磷脂水平（nmol/mg蛋白）在nBM异博定酸损伤侧也随之降低（13%，p < 0.05，n = 14），而nBM假损伤后则无差异。与对照组织相比，nBM异博定酸损伤的额叶皮质组织中的胆碱和GPC水平也降低（胆碱：21%，p < 0.05，n = 14；GPC：10%，p < 0.05，n = 14），而nBM假损伤则无影响。通过卡巴胆碱刺激的肌醇磷酸生成量测量发现，nBM异博定酸损伤后额叶皮质中的毒蕈碱受体敏感性增加（p < 0.001，n = 12），这表明nBM异博定酸损伤后皮质中可能会发生受体介导的磷脂水解增加。这些数据表明，胆碱能传递受损会改变胆碱能靶区域的磷脂代谢。
