TY - JOUR
T1 - Cajal-Retzius cells instruct neuronal migration by coincidence signaling between secreted and contact-dependent guidance cues
AU - Gil-Sanz, Cristina
AU - Franco, Santos J.
AU - Martinez-Garay, Isabel
AU - Espinosa, Ana
AU - Harkins-Perry, Sarah
AU - Müller, Ulrich
N1 - Funding Information:
We thank K. Spencer for help with microscopy; C. Ramos, G. Martin, and S. Kupriyanov for assistance with generating mice; and the Polleux laboratory for reagents. This work was supported by funding from the NIH (NS060355 to S.J.F.; NS046456, MH078833, and HD070494 to U.M.), the Dorris Neurscience Center (U.M.), the Skaggs Institute for Chemical Biology (U.M.), CIRM (I.M.-G. and A.E.), Ministerio de Educacion (EX2009-0416 to C.G.-S.; FU-2006-1238 to I.M.-G.), and Generalitat Valenciana (APOSTD/2010/064 to C.G.-S.).
PY - 2013/8/7
Y1 - 2013/8/7
N2 - 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
AB - 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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U2 - 10.1016/j.neuron.2013.06.040
DO - 10.1016/j.neuron.2013.06.040
M3 - Article
C2 - 23931996
AN - SCOPUS:84881526677
SN - 0896-6273
VL - 79
SP - 461
EP - 477
JO - Neuron
JF - Neuron
IS - 3
ER -