• 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

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
Issue number6423
Publication statusPublished - 11 Jan 2019

ID: 43964822