Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Neuron. 2013 Aug 7;79(3):447-60. doi: 10.1016/j.neuron.2013.05.035.
The convergence of APP (substrate) and BACE-1 (enzyme) is a rate-limiting, obligatory event triggering the amyloidogenic pathway-a key step in Alzheimer's disease (AD) pathology. However, as both APP/BACE-1 are highly expressed in brain, mechanisms precluding their unabated convergence are unclear. Exploring dynamic localization of APP/BACE-1 in cultured hippocampal neurons, we found that after synthesis via the secretory pathway, dendritic APP/BACE-1-containing vesicles are largely segregated in physiologic states. While BACE-1 is sorted into acidic recycling endosomes, APP is conveyed in Golgi-derived vesicles. However, upon activity induction-a known trigger of the amyloidogenic pathway-APP is routed into BACE-1-positive recycling endosomes via a clathrin-dependent mechanism. A partitioning/convergence of APP/BACE-1 vesicles is also apparent in control/AD brains, respectively. Considering BACE-1 is optimally active in an acidic environment, our experiments suggest that neurons have evolved trafficking strategies that normally limit APP/BACE-1 proximity and also uncover a pathway routing APP into BACE-1-containing organelles, triggering amyloidogenesis.
淀粉样前体蛋白（APP）和β-分泌酶 1（BACE-1）的聚合是触发淀粉样蛋白生成途径的限速、必需事件——这是阿尔茨海默病（AD）病理学的关键步骤。然而，由于 APP/BACE-1 在大脑中均高度表达，阻止其无限制聚合的机制尚不清楚。在培养的海马神经元中探索 APP/BACE-1 的动态定位时，我们发现 APP/BACE-1 包含的囊泡在合成后通过分泌途径运输，在生理状态下基本是分开的。虽然 BACE-1 被分拣到酸性再循环内体中，但 APP 则被运送到高尔基衍生的囊泡中。然而，在活性诱导（已知的淀粉样蛋白生成途径的触发因素）下，APP 通过网格蛋白依赖性机制被路由到 BACE-1 阳性的再循环内体中。APP/BACE-1 囊泡的分隔/聚合在对照/AD 大脑中也很明显。鉴于 BACE-1 在酸性环境中具有最佳活性，我们的实验表明，神经元已经进化出了运输策略，这些策略通常限制 APP/BACE-1 的接近，并揭示了一种将 APP 路由到包含 BACE-1 的细胞器中的途径，从而引发淀粉样蛋白生成。
