Bigl M, Apelt J, Eschrich K, Schliebs R
Institute of Biochemistry, University of Leipzig, Leipzig, Germany.
J Neural Transm (Vienna). 2003 Jan;110(1):77-94. doi: 10.1007/s00702-002-0772-x.
Alzheimer's disease is associated with markedly impaired cerebral glucose metabolism as detected by reduced cortical desoxyglucose utilization, by altered activities of key glycolytic enzymes or by reduced densities of cortical glucose transporter subtypes. To determine whether formation and/or deposition of beta-amyloid plays a role in the pathology of glucose metabolism, transgenic Tg2576 mice that overexpress the Swedish mutation of the human amyloid precursor protein and demonstrate a progressive, age-related cortical and hippocampal deposition of beta-amyloid plaques, were used to study expression and activity of key enzymes of brain glycolysis (phosphofructokinase, PFK) and glyconeogenesis (fructose1,6-bisphosphatase; FbPase). Quantitative RT-PCR revealed high expression levels of both C- and M-type PFK mRNA in non-transgenic mouse cerebral cortex, whilst there was little expression of the L-type. In 24-month-old transgenic Tg2576 mouse cortex, but not in 7-, 13-, and 17-month-old mice, the copy number of PFK-C mRNA was significantly reduced in comparison to non-transgenic littermates, while the mRNA level of the other PFK isoforms and FbPase did not differ between transgenic and non-transgenic tissue samples. In situ hybridization in brain sections from aged Tg2576 mice revealed reduced PFK-C mRNA expression in beta-amyloid plaque-associated neurons and upregulation in reactive astrocytes surrounding beta-amyloid deposits. The decreased PFK-C protein level detected by Western analysis in cerebral cortical tissue from 24-month-old transgenic Tg2576 mice was accompanied by reduced enzyme activity of PFK in comparison to non-transgenic littermates. Our data demonstrate that impairment of cerebral cortical glucose metabolism occurs only due to the long-lasting high beta-amyloid burden. This results from a reduction in glycolytic activity in beta-amyloid plaque-associated neurons and a concomitant upregulation in reactive, plaque-surrounding astrocytes.
阿尔茨海默病与显著受损的脑葡萄糖代谢相关，这可通过皮质脱氧葡萄糖利用率降低、关键糖酵解酶活性改变或皮质葡萄糖转运体亚型密度降低来检测。为了确定β-淀粉样蛋白的形成和/或沉积是否在葡萄糖代谢病理学中起作用，使用了过表达人类淀粉样前体蛋白瑞典突变且表现出β-淀粉样斑块进行性、年龄相关的皮质和海马沉积的转基因Tg2576小鼠，来研究脑糖酵解（磷酸果糖激酶，PFK）和糖异生（果糖1,6-二磷酸酶；FbPase）关键酶的表达和活性。定量逆转录聚合酶链反应显示，在非转基因小鼠大脑皮质中，C型和M型PFK mRNA均有高表达水平，而L型几乎没有表达。在24月龄转基因Tg2576小鼠皮质中，与非转基因同窝小鼠相比，PFK-C mRNA拷贝数显著降低，但在7、13和17月龄小鼠中未出现这种情况，而其他PFK同工型和FbPase的mRNA水平在转基因和非转基因组织样本之间没有差异。对老年Tg2576小鼠脑切片进行原位杂交显示，β-淀粉样斑块相关神经元中PFK-C mRNA表达降低，而β-淀粉样沉积物周围的反应性星形胶质细胞中表达上调。通过蛋白质免疫印迹分析检测到，24月龄转基因Tg2576小鼠大脑皮质组织中PFK-C蛋白水平降低，同时与非转基因同窝小鼠相比，PFK酶活性降低。我们的数据表明，仅由于长期高β-淀粉样蛋白负荷才会发生大脑皮质葡萄糖代谢受损。这是由于β-淀粉样斑块相关神经元中的糖酵解活性降低以及斑块周围反应性星形胶质细胞中的糖酵解活性同时上调所致。
