Activity-induced convergence of APP and BACE-1 in acidic microdomains via an endocytosis-dependent pathway.
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.
Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Utpal
U
Das
David A
DA
Scott
Archan
A
Ganguly
Edward H
EH
Koo
Yong
Y
Tang
Subhojit
S
Roy
D000544:Alzheimer Disease / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002966:Clathrin / Q000235:genetics / Q000378:metabolism; D022163:Clathrin-Coated Vesicles / Q000187:drug effects / Q000502:physiology; D004705:Endocytosis / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D005998:Glycine / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D006863:Hydrogen-Ion Concentration; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000648:ultrastructure*; D009924:Organ Culture Techniques; D010852:Picrotoxin / Q000494:pharmacology; D021381:Protein Transport / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor; D016282:Aspartic Acid Endopeptidases; D002966:Clathrin; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D005998:Glycine; D009419:Nerve Tissue Proteins; D010852:Picrotoxin; D020696:rab5 GTP-Binding Proteins; C509282:Bace1 protein, mouse