Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, SA, Australia.
J Neurochem. 2012 Sep;122(5):1010-22. doi: 10.1111/j.1471-4159.2012.07845.x.
Amyloid precursor protein (APP) is involved in the pathogenesis of Alzheimer's disease. It is axonally transported, endocytosed and sorted to different cellular compartments where amyloid beta (Aβ) is produced. However, the mechanism of APP trafficking remains unclear. We present evidence that huntingtin associated protein 1 (HAP1) may reduce Aβ production by regulating APP trafficking to the non-amyloidogenic pathway. HAP1 and APP are highly colocalized in a number of brain regions, with similar distribution patterns in both mouse and human brains. They are associated with each other, the interacting site is the 371-599 of HAP1. APP is more retained in cis-Golgi, trans-Golgi complex, early endosome and ER-Golgi intermediate compartment in HAP1-/- neurons. HAP1 deletion significantly alters APP endocytosis and reduces the re-insertion of APP into the cytoplasmic membrane. Amyloid precursor protein-YFP(APP-YFP) vesicles in HAP1-/- neurons reveal a decreased trafficking rate and an increased number of motionless vesicles. Knock-down of HAP1 protein in cultured cortical neurons of Alzheimer's disease mouse model increases Aβ levels. Our data suggest that HAP1 regulates APP subcellular trafficking to the non-amyloidogenic pathway and may negatively regulate Aβ production in neurons.
淀粉样前体蛋白（APP）参与阿尔茨海默病的发病机制。它被轴突运输，内吞和分拣到不同的细胞区室，在那里产生淀粉样β（Aβ）。然而，APP 运输的机制尚不清楚。我们提出证据表明，亨廷顿相关蛋白 1（HAP1）可以通过调节 APP 向非淀粉样形成途径的运输来减少 Aβ的产生。HAP1 和 APP 在许多脑区高度共定位，在小鼠和人脑中有相似的分布模式。它们相互关联，相互作用的位点是 HAP1 的 371-599。在 HAP1-/-神经元中，APP 在顺式高尔基体、高尔基复合体、早期内体和 ER-Golgi 中间隔室中保留更多。HAP1 缺失显著改变 APP 的内吞作用，并减少 APP 重新插入细胞质膜。HAP1-/-神经元中的淀粉样前体蛋白-YFP（APP-YFP）囊泡显示出转运率降低和静止囊泡数量增加。在阿尔茨海默病小鼠模型的培养皮质神经元中敲低 HAP1 蛋白会增加 Aβ水平。我们的数据表明，HAP1 调节 APP 的细胞内运输到非淀粉样形成途径，并可能负调节神经元中的 Aβ产生。
