Department of Biochemistry, Ewha Womans University School of Medicine, Seoul 158-710, Korea.
BMB Rep. 2010 Oct;43(10):704-9. doi: 10.5483/BMBRep.2010.43.10.704.
The Swedish mutation (K595N/M596L) of amyloid precursor protein (APP-swe) has been known to increase abnormal cleavage of cellular APP by Beta-secretase (BACE), which causes tau protein hyperphosphorylation and early-onset Alzheimer's disease (AD). Here, we analyzed the effect of APP-swe in global gene expression using deep transcriptome sequencing technique. We found 283 genes were down-regulated and 348 genes were up-regulated in APP-swe expressing H4-swe cells compared to H4 wild-type cells from a total of approximately 74 million reads of 38 base pairs from each transcriptome. Two independent mechanisms such as kinase and phosphatase signaling cascades leading hyperphosphorylation of tau protein were regulated by the expression of APP-swe. Expressions of catalytic subunit as well as several regulatory subunits of protein phosphatases 2A were decreased. In contrast, expressions of tau-phosphorylating glycogen synthase kinase 3ß (GSK-3ß), cyclin dependent kinase 5 (CDK5), and cAMP-dependent protein kinase A (PKA) catalytic subunit were increased. Moreover, the expression of AD-related Aquaporin 1 and presenilin 2 expression was regulated by APP-swe. Taken together, we propose that the expression of APP-swe modulates global gene expression directed to AD pathogenesis.
淀粉样前体蛋白（APP）的瑞典突变（K595N/M596L）已知会增加β-分泌酶（BACE）对细胞 APP 的异常切割，从而导致tau 蛋白过度磷酸化和早发性阿尔茨海默病（AD）。在这里，我们使用深度转录组测序技术分析了 APP-swe 对全局基因表达的影响。我们发现与 H4 野生型细胞相比，在 APP-swe 表达的 H4-swe 细胞中，有 283 个基因下调，348 个基因上调，每个转录组的 38 个碱基的总读数约为 7400 万。两种独立的机制，如激酶和磷酸酶信号级联，导致 tau 蛋白过度磷酸化，这两种机制受到 APP-swe 的表达调节。蛋白磷酸酶 2A 的催化亚基和几个调节亚基的表达减少。相比之下，tau 磷酸化糖原合酶激酶 3β（GSK-3β）、细胞周期蛋白依赖性激酶 5（CDK5）和 cAMP 依赖性蛋白激酶 A（PKA）催化亚基的表达增加。此外，AD 相关水通道蛋白 1和早老素 2 的表达也受到 APP-swe 的调节。总之，我们提出 APP-swe 的表达调节了 AD 发病机制的全局基因表达。
