Activity-Induced Convergence of APP and BACE-1 in Acidic Microdomains via an Endocytosis-Dependent Pathway

被引：184

作者：

Das, Utpal ^{[1
,2
]}

Scott, David A. ^{[1
,2
]}

Ganguly, Archan ^{[1
,2
]}

Koo, Edward H. ^{[2
]}

Tang, Yong ^{[1
,2
]}

Roy, Subhojit ^{[1
,2
]}

机构：

[1] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA

[2] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

来源：

NEURON | 2013年 / 79卷 / 03期

关键词：

AMYLOID PRECURSOR PROTEIN; CULTURED HIPPOCAMPAL-NEURONS; ALZHEIMERS-DISEASE; IN-VIVO; RECYCLING ENDOSOMES; AXONAL-TRANSPORT; SYNAPTIC FUNCTION; AMPA RECEPTORS; BETA; TRAFFICKING;

D O I：

10.1016/j.neuron.2013.05.035

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：447 / 460

页数：14

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