@article{45270141d3a6437b8e2465c0a8867924,
title = "Antagonistic Effects of BACE1 and APH1B-γ-Secretase Control Axonal Guidance by Regulating Growth Cone Collapse",
abstract = "BACE1 is the major drug target for Alzheimer's disease, but we know surprisingly little about its normal function in the CNS. Here, we show that this protease is critically involved in semaphorin 3A (Sema3A)-mediated axonal guidance processes in thalamic and hippocampal neurons. An active membrane-bound proteolytic CHL1 fragment is generated by BACE1 upon Sema3A binding. This fragment relays the Sema3A signal via ezrin-radixin-moesin (ERM) proteins to the neuronal cytoskeleton. APH1B-γ-secretase-mediated degradation of this fragment stops the Sema3A-induced collapse and sensitizes the growth cone for the next axonal guidance cue. Thus, we reveal a cycle of proteolytic activity underlying growth cone collapse and restoration used by axons to find their correct trajectory in the brain. Our data also suggest that BACE1 and γ-secretase inhibition have physiologically opposite effects in this process, supporting the idea that combination therapy might attenuate some of the side effects associated with these drugs.",
author = "Soraia Bar{\~a}o and Annette G{\"a}rtner and Eduardo Leyva-D{\'i}az and Galina Demyanenko and Sebastian Munck and Tine Vanhoutvin and Lujia Zhou and Melitta Schachner and Guillermina L{\'o}pez-Bendito and Maness, {Patricia F.} and {De Strooper}, Bart",
note = "Funding Information: Dr. Joris De Wit is thanked for critical discussion and providing Sema3A-RFP expression construct. This work was supported by the European Research Council (ERC) grant ERC-2009-StG_20081210 to G.L.-B. and ERC-2010-AG_268675 to B.D.S., the Fonds voor Wetenschappelijk Onderzoek (FWO), the KU Leuven and VIB, a Methusalem grant of the KU Leuven/Flemish Government to B.D.S., and a Funda{\c c}{\~a}o para a Ci{\^e}ncia e a Tecnologia (FCT) POPH/FSE/FCT/SFRH/BD/71949/2010 grant to S.B. G.L.-B. is an EMBO YIP Investigator. B.D.S. is supported by the Bax-Vanluffelen Chair for Alzheimer{\textquoteright}s Disease and “Opening the Future” of the Leuven Universiteit Fonds (LUF). Confocal microscope equipment was acquired through a Hercules Type 1 AKUL/09/037 to W. Annaert. The Zeiss ELYRA S1 (SR-SIM) super-resolution microscope was acquired through a CLME grant from minister Lieten to the VIB Bioimaging Core facility. Mouse experiments were supported by Inframouse. B.D.S. is a consultant for Janssen Pharmaceutica, Forum Pharmaceuticals, and Remynd NV. Publisher Copyright: {\textcopyright} 2015 The Authors.",
year = "2015",
month = sep,
day = "1",
doi = "10.1016/j.celrep.2015.07.059",
language = "English (US)",
volume = "12",
pages = "1367--1376",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "9",
}