Mastrogiacoma F, Lindsay J G, Bettendorff L, Rice J, Kish S J
Human Neurochemical Pathology Laboratory, Clarke Institute of Psychiatry, Toronto, Canada.
Ann Neurol. 1996 May;39(5):592-8. doi: 10.1002/ana.410390508.
To determine whether the reduction in brain alpha-ketoglutarate dehydrogenase complex activity in Alzheimer's disease (AD) is associated with an abnormality in one of its three constituent enzyme subunits, we measured protein levels of alpha-ketoglutarate dehydrogenase (El), dihydrolipoamide succinyltransferase (E2), and dihydrolipoamide dehydrogenase (E3), in postmortem brain of 29 patients with AD (mean age, 73 years; age range of onset, 50-78 years) and 29 control subjects. In the AD group protein levels of all three subunits were significantly reduced by 23 to 41% in the temporal cortex, whereas in the parietal cortex (El: -28%; E3: -32%) and hippocampus (E3: -33%) significant changes were limited to El and E3. alpha-Ketoglutarate dehydrogenase complex activities were more markedly reduced (by 46-68%) and did not correlate with protein levels, suggesting that decreased enzyme activity cannot be primarily explained by loss of alpha-ketoglutarate dehydrogenase complex protein. We did not find two E2 immunoreactive forms in the brain of any patient, as has been reported in fibroblasts of patients with very-early-onset chromosome 14-linked AD. We conclude that brain protein and activity levels of alpha-ketoglutarate dehydrogenase complex are reduced in patients with AD who have onset after 50 years and suggest that these changes, which are also observed in other human brain disorders, may represent a nonspecific consequence of different neurodegenerative processes. Nevertheless, reduced levels of this rate-limiting enzyme of the Krebs cycle could contribute to the brain neurodegenerative mechanisms of AD.
为了确定阿尔茨海默病（AD）患者脑内α-酮戊二酸脱氢酶复合体活性降低是否与其三个组成酶亚基之一的异常有关，我们检测了29例AD患者（平均年龄73岁；发病年龄范围50 - 78岁）和29例对照者死后大脑中α-酮戊二酸脱氢酶（El）、二氢硫辛酰胺琥珀酰转移酶（E2）和二氢硫辛酰胺脱氢酶（E3）的蛋白水平。在AD组中，颞叶皮质中所有三个亚基的蛋白水平均显著降低了23%至41%，而在顶叶皮质（El：-28%；E3：-32%）和海马体（E3：-33%）中，显著变化仅限于El和E3。α-酮戊二酸脱氢酶复合体活性降低更为明显（降低了46% - 68%），且与蛋白水平不相关，这表明酶活性降低不能主要用α-酮戊二酸脱氢酶复合体蛋白的缺失来解释。我们在任何患者的大脑中均未发现两种E2免疫反应形式，而在极早发型14号染色体连锁AD患者的成纤维细胞中曾有过相关报道。我们得出结论，50岁以后发病的AD患者脑内α-酮戊二酸脱氢酶复合体的蛋白和活性水平降低，并且这些变化在其他人类脑部疾病中也有观察到，可能代表了不同神经退行性过程的非特异性后果。尽管如此，三羧酸循环中这种限速酶水平的降低可能有助于AD的脑内神经退行性机制。
