Cortical glucose metabolism is altered in aged transgenic Tg2576 mice that demonstrate Alzheimer plaque pathology
Cortical glucose metabolism is altered in aged transgenic Tg2576 mice that demonstrate Alzheimer plaque pathology
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DOI：
10.1007/s00702-002-0772-x
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发表时间：
2003-01-01
影响因子：
3.3
通讯作者：
Schliebs, R
中科院分区：
文献类型：
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作者：
Bigl, M;Apelt, J;Schliebs, R
阿尔茨海默病与大脑葡萄糖代谢显着受损有关，通过皮质脱氧葡萄糖利用减少、关键糖酵解酶活性改变或皮质葡萄糖转运蛋白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的病理学中发挥作用，转基因Tg2576小鼠过度表达人类淀粉样蛋白前体蛋白的瑞典突变，并表现出β-淀粉样蛋白斑块的渐进性、与年龄相关的皮质和海马沉积，用于研究脑糖酵解（磷酸果糖激酶，PFK）和糖异生（果糖）关键酶的表达和活性1,6-双磷酸酶；FbPase)。定量RT-PCR显示非转基因小鼠大脑皮层中G型和M型PFK mRNA高表达，而L型表达很少。在 24 个月大的转基因 Tg2576 小鼠皮质中，与非转基因同窝小鼠相比，PFK-C mRNA 的拷贝数显着减少，而在 7、13 和 17 个月大的小鼠中则不然，而其他 PFK 亚型和 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 小鼠脑切片的原位杂交显示，β-淀粉样斑块相关神经元中 PFK-C mRNA 表达降低，β-淀粉样沉积物周围的反应性星形胶质细胞表达上调。与非转基因同窝小鼠相比，Western 分析检测到 24 个月大转基因 Tg2576 小鼠大脑皮层组织中 PFK-C 蛋白水平降低，同时 PFK 酶活性降低。我们的数据表明，大脑皮质葡萄糖代谢受损仅是由于长期持续的高β-淀粉样蛋白负担而发生。这是由于β-淀粉样斑块相关神经元中糖酵解活性的降低以及斑块周围反应性星形胶质细胞的相应上调所致。
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 (fructose 1,6-bisphosphatase; FbPase). Quantitative RT-PCR revealed high expression levels of both G 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 comparisonto 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.