@article{3b7cc050590948cba9382ab50ab5361f,
title = " Secreted amyloid-b precursor protein functions as a GABA B R1a ligand to modulate synaptic transmission ",
abstract = " Amyloid-b precursor protein (APP) is central to the pathogenesis of Alzheimer{\textquoteright}s disease, yet its physiological function remains unresolved. Accumulating evidence suggests that APP has a synaptic function mediated by an unidentified receptor for secreted APP (sAPP). Here we show that the sAPP extension domain directly bound the sushi 1 domain specific to the g-aminobutyric acid type B receptor subunit 1a (GABA B R1a). sAPP-GABA B R1a binding suppressed synaptic transmission and enhanced short-term facilitation in mouse hippocampal synapses via inhibition of synaptic vesicle release. A 17–amino acid peptide corresponding to the GABA B R1a binding region within APP suppressed in vivo spontaneous neuronal activity in the hippocampus of anesthetized Thy1-GCaMP6s mice. Our findings identify GABA B R1a as a synaptic receptor for sAPP and reveal a physiological role for sAPP in regulating GABA B R1a function to modulate synaptic transmission.",
author = "Rice, {Heather C.} and {De Malmazet}, Daniel and An Schreurs and Samuel Frere and {Van Molle}, Inge and Volkov, {Alexander N.} and Eline Creemers and Irena Vertkin and Julie Nys and Ranaivoson, {Fanomezana M.} and Davide Comoletti and Savas, {Jeffrey N.} and Han Remaut and Detlef Balschun and Wierda, {Keimpe D.} and Inna Slutsky and Karl Farrow and {De Strooper}, Bart and {De Wit}, Joris",
note = "Funding Information: We thank G. Conway, A. Snellinx, K. Craessaerts, K. Horr{\'e}, K. Vennekens, V. Hendrickx, and J. Verwaeren for technical help. We thank C. Martin, N. Ap{\'o}stolo, G. Condomitti, G. Marcassa, and I. Chrysidou for experimental assistance. We thank L. Buts for help with NMR structure calculations; M. A. Busche for advice on in vivo calcium imaging experiments; P. Vanderheyden, S. Zels, I. Beets, L. Schoofs, H. Dunn, and K. Martemyanov for advice on and/or performing G protein–coupled receptor activity experiments; and U. Mueller for the App/Aplp1 double KO mice. This work was supported by an Alzheimer{\textquoteright}s Association Research Fellowship (AARF-16-442885, H.C.R.); Stichting Voor Alzheimer Onderzoek Pilot Grant (16011, H.C.R.); Agency for Innovation by Science and Technology in Flanders (IWT 141698, A.S.); National Science Foundation BRAIN EAGER MCB-1450895 and IOS-1755189 (D.C.); Robert Wood Johnson Foundation grant no. 74260 to the Child Health Institute of New Jersey (D.C.); RO1AG061787 (J.N.S.); VUB onderzoeksfonds (SRP13, H.R.); European Research Council (ERC) (724866, I.S.); FWO Project Grant G.0946.16N (K.F.); Vlaams Initiatief voor Netwerken voor Dementie Onderzoek (VIND, Strategic Basic Research Grant 135043, B.D.S.); FWO Project Grant G.0D98.17N (B.D.S.); KU Leuven Methusalem Grant (B.D.S. and J.d.W.); ERC Starting Grant (311083, J.d.W.); FWO Odysseus Grant (J.d.W.); and FWO Project Grant G.0654.15N (J.d.W.). B.D.S. is supported by the Arthur Bax and Anna Vanluffelen chair for Alzheimer{\textquoteright}s disease, “Opening the Future” of the Leuven Universiteit Fonds (LUF), and by the “Geneeskundige Stichting Koningin Elisabeth.” Publisher Copyright: {\textcopyright} 2017 The Authors.",
year = "2019",
month = jan,
day = "11",
doi = "10.1126/science.aao4827",
language = "English (US)",
volume = "363",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6423",
}