Johnston J A, Norgren S, Ravid R, Wasco W, Winblad B, Lannfelt L, Cowburn R F
Department of Clinical Neuroscience and Family Medicine, Karolinska Institute, Novum KFC, Huddinge, Sweden.
Brain Res Mol Brain Res. 1996 Dec 31;43(1-2):85-95. doi: 10.1016/s0169-328x(96)00161-1.
Amyloid precursor protein (APP) is metabolised to produce A beta, a peptide found aggregated in Alzheimer's disease neuritic plaques. APP is a member of a multigene protein family which includes amyloid precursor-like protein 2 (APLP2). Since A beta accumulation can be triggered by factors acting up- or downstream of APP processing, we investigated whether APP mRNA expression was altered in Alzheimer's disease post-mortem cerebral cortex. In addition, we characterised cortical APLP2 mRNA levels. Quantitative RNA-RNA solution hybridisation-RNase protection was used to assay total APP. APP containing the Kunitz-type protease inhibitor (KPI) insert and APLP2 mRNA in mid-temporal and superior frontal cortices from apolipoprotein E-genotyped subjects with Alzheimer's disease, other neurological diseases and non-demented controls. Approximately 3 times more APP than APLP2 mRNA was detected and about 70% of total APP mRNA contained the KPI insert in the control subjects. Total APP and APLP2 mRNA levels were significantly reduced in Alzheimer's disease mid-temporal, but not superior frontal cortex, suggesting that regional reductions in these mRNA correlate with severity of disease pathology. A small significant increase in the proportion of APP KPI mRNA was seen in both cortical regions in Alzheimer's disease. Apolipoprotein E genotype did not influence cortical levels of total APP, APP KPI or APLP2 mRNA. Alzheimer's disease-related increases in tissue DNA content were seen in both regions studied, while tissue RNA levels were reduced in the positive disease controls. In summary, these results indicate that Alzheimer's disease is not associated with over-expression of either APP or APLP2 mRNA. Our findings reveal a disease-associated increase in the proportion of APP KPI-containing isoforms, and further investigation should clarify whether this predisposes affected individuals to A beta production and aggregation, or reflects later events such as gliosis and neuronal cell death.
淀粉样前体蛋白（APP）经代谢产生β-淀粉样蛋白（Aβ），该肽在阿尔茨海默病神经炎性斑块中呈聚集状态。APP是一个多基因蛋白家族的成员，该家族包括淀粉样前体样蛋白2（APLP2）。由于Aβ的积累可由作用于APP加工过程上游或下游的因素触发，我们研究了APP mRNA表达在阿尔茨海默病尸检大脑皮质中是否发生改变。此外，我们对皮质APLP2 mRNA水平进行了特征分析。采用定量RNA-RNA溶液杂交-核糖核酸酶保护法检测总APP。对载脂蛋白E基因分型的阿尔茨海默病患者、其他神经疾病患者及非痴呆对照者颞中回和额上回皮质中含库尼茨型蛋白酶抑制剂（KPI）插入片段的APP及APLP2 mRNA进行检测。在对照受试者中，检测到的APP mRNA约为APLP2 mRNA的3倍，且总APP mRNA的约70%含有KPI插入片段。阿尔茨海默病患者颞中回皮质中总APP和APLP2 mRNA水平显著降低，但额上回皮质未降低，提示这些mRNA的区域减少与疾病病理严重程度相关。在阿尔茨海默病患者的两个皮质区域中，APP KPI mRNA的比例均有小幅显著增加。载脂蛋白E基因型不影响皮质中总APP、APP KPI或APLP2 mRNA水平。在研究的两个区域中均观察到与阿尔茨海默病相关的组织DNA含量增加，而在阳性疾病对照中组织RNA水平降低。总之，这些结果表明阿尔茨海默病与APP或APLP2 mRNA的过表达无关。我们的研究结果揭示了含APP KPI异构体比例与疾病相关的增加，进一步研究应阐明这是否使受影响个体易发生Aβ的产生和聚集，或反映诸如胶质增生和神经元细胞死亡等后期事件。
