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.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Video-Audio Media
MeSH terms
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Alzheimer Disease / pathology
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Amyloid Precursor Protein Secretases / genetics
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Amyloid Precursor Protein Secretases / metabolism*
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Amyloid beta-Protein Precursor / metabolism*
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Animals
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Animals, Newborn
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Aspartic Acid Endopeptidases / genetics
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Aspartic Acid Endopeptidases / metabolism*
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Brain / metabolism
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Brain / pathology
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Case-Control Studies
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Clathrin / genetics
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Clathrin / metabolism
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Clathrin-Coated Vesicles / drug effects
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Clathrin-Coated Vesicles / physiology
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Endocytosis / physiology*
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Enzyme Inhibitors / pharmacology
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Excitatory Amino Acid Antagonists / pharmacology
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GABA Antagonists / pharmacology
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Glycine / pharmacology
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Hippocampus / cytology
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Hydrogen-Ion Concentration
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Membrane Microdomains / metabolism*
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Mice
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neurons / ultrastructure*
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Organ Culture Techniques
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Picrotoxin / pharmacology
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Protein Transport / physiology
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Signal Transduction / physiology*
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rab5 GTP-Binding Proteins / metabolism
Substances
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Amyloid beta-Protein Precursor
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Clathrin
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Enzyme Inhibitors
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Excitatory Amino Acid Antagonists
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GABA Antagonists
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Nerve Tissue Proteins
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Picrotoxin
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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Bace1 protein, mouse
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rab5 GTP-Binding Proteins
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Glycine