期刊
NEURON
卷 79, 期 3, 页码 447-460出版社
CELL PRESS
DOI: 10.1016/j.neuron.2013.05.035
关键词
-
资金
- American Federation for Aging Research (AFAR)
- NIH [P50AG005131]
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.
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