Donev R, Newall A, Thome J, Sheer D
Human Cytogenetics Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, London, UK.
Mol Psychiatry. 2007 Jul;12(7):681-90. doi: 10.1038/sj.mp.4001971. Epub 2007 Mar 13.
The beta-amyloid peptide (Abeta) that accumulates in senile plaques in Alzheimer's disease is formed by cleavage of the amyloid precursor protein (APP). The APP gene has several intronic Alu elements inserted in either the sense or antisense orientation. In this study, we demonstrate that binding of SC35 and hnRNPA1 to Alu elements on either side of exon 7 in the transcribed pre-mRNA is involved in alternative splicing of APP exons 7 and 8. Neuronal cells transfected with the full-length form of APP secrete higher levels of Abeta than cells transfected with the APP695 isoform lacking exons 7 and 8. Finally, we show that treatment of neuronal cells with estradiol results in increased expression of APP695, SC35 and hnRNPA1, and lowers the level of secreted Abeta. An understanding of the regulation of splicing of APP may lead to the identification of new targets for treating Alzheimer's disease.
在阿尔茨海默病的老年斑中积累的β-淀粉样肽（Aβ）是由淀粉样前体蛋白（APP）的切割形成的。APP基因有几个内含子Alu元件，以正义或反义方向插入。在本研究中，我们证明SC35和hnRNPA1与转录的前体mRNA中外显子7两侧的Alu元件结合，参与APP外显子7和8的可变剪接。用全长形式的APP转染的神经元细胞比用缺乏外显子7和8的APP695异构体转染的细胞分泌更高水平的Aβ。最后，我们表明用雌二醇处理神经元细胞会导致APP695、SC35和hnRNPA1的表达增加，并降低分泌的Aβ水平。对APP剪接调控的理解可能会导致识别出治疗阿尔茨海默病的新靶点。
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