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Neuron. 2013 Aug 7;79(3):447-60. doi: 10.1016/j.neuron.2013.05.035.

Activity-induced convergence of APP and BACE-1 in acidic microdomains via an endocytosis-dependent pathway.

Author information

1
Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

Abstract

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.

PMID:
23931995
PMCID:
PMC3741682
DOI:
10.1016/j.neuron.2013.05.035
[Indexed for MEDLINE]
Free PMC Article

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