Secreted amyloid-β precursor protein functions as a GABABR1a ligand to modulate synaptic transmission

Heather C Rice, Daniel de Malmazet, An Schreurs, Samuel Frere, Inge Van Molle, Alexander N Volkov, Eline Creemers, Irena Vertkin, Julie Nys, Fanomezana M Ranaivoson, Davide Comoletti, Jeffrey N Savas, Han Remaut, Detlef Balschun, Keimpe D Wierda, Inna Slutsky, Karl Farrow, Bart De Strooper, Joris de Wit

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

Amyloid-β precursor protein (APP) is central to the pathogenesis of Alzheimer'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 γ-aminobutyric acid type B receptor subunit 1a (GABABR1a). sAPP-GABABR1a 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 GABABR1a binding region within APP suppressed in vivo spontaneous neuronal activity in the hippocampus of anesthetized Thy1-GCaMP6s mice. Our findings identify GABABR1a as a synaptic receptor for sAPP and reveal a physiological role for sAPP in regulating GABABR1a function to modulate synaptic transmission.

Original languageEnglish
Article numbereaao4827
Pages (from-to)1-7
Number of pages7
JournalScience
Volume363
Issue number6423
DOIs
Publication statusPublished - 11 Jan 2019

Bibliographical note

Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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