Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, The Biomedical Centre, Box 575, 75123 Uppsala, Sweden.
Biochem Biophys Res Commun. 2010 Mar 12;393(3):356-61. doi: 10.1016/j.bbrc.2009.12.122. Epub 2009 Dec 28.
In Alzheimer's disease the amyloid beta-peptide (Abeta) aggregates in brain tissue and arteries. Abeta is proteolytically cleaved out from amyloid precursor protein (APP) by different secretases. Recently, the transmembrane protein ITM2B/Bri2, which is expressed in neurons and associated with familial British and Danish dementia, was shown to inhibit APP processing in transfected cells as well as in transgenic mice. Several mechanisms by which Bri2 can interfere with Abeta production and aggregation have been proposed. Herein, we studied recombinant human Bri2 (residues 90-236) containing the extracellular Brichos domain without the ABri23 peptide. Bri2(90-236) binds to ABri23, which suggests that these two parts interact during Bri2 biosynthesis, in line with proposed functions of Brichos domains in other proteins. Moreover, Bri2(90-236) binds Abeta1-40 and inhibits its aggregation and fibril formation. These data suggest a model for how the processing of Bri2 and APP are interrelated.
在阿尔茨海默病中，淀粉样β肽（Abeta）在脑组织和动脉中聚集。Abeta 通过不同的蛋白酶从淀粉样前体蛋白（APP）中蛋白水解切割出来。最近，跨膜蛋白 ITM2B/Bri2 在神经元中表达，与家族性英国和丹麦痴呆症有关，研究表明它可以抑制转染细胞和转基因小鼠中的 APP 加工。已经提出了 Bri2 可以干扰 Abeta 产生和聚集的几种机制。在此，我们研究了含有细胞外 Brichos 结构域但不含 ABri23 肽的重组人 Bri2（残基 90-236）。Bri2（90-236）与 ABri23 结合，这表明这两个部分在 Bri2 生物合成过程中相互作用，符合其他蛋白质中 Brichos 结构域的功能。此外，Bri2（90-236）与 Abeta1-40 结合并抑制其聚集和纤维形成。这些数据表明了 Bri2 和 APP 加工如何相互关联的模型。
