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Science. 2019 Jan 11;363(6423). pii: eaao4827. doi: 10.1126/science.aao4827.

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

Author information

1
VIB Center for Brain & Disease Research, Leuven, Belgium.
2
Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium.
3
Neuro-Electronics Research Flanders, Leuven, Belgium.
4
Department of Biology, Leuven Brain Institute, KU Leuven, Leuven, Belgium.
5
Brain & Cognition, KU Leuven, Leuven, Belgium.
6
Department of Physiology and Pharmacology, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
7
VIB-VUB Structural Biology Research Center, Brussels, Belgium.
8
Jean Jeener NMR Centre, VUB, Brussels, Belgium.
9
Child Health Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, NJ, USA.
10
Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, NJ, USA.
11
Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
12
VIB, Leuven, Belgium.
13
imec, Leuven, Belgium.
14
VIB Center for Brain & Disease Research, Leuven, Belgium. bart.destrooper@kuleuven.vib.be joris.dewit@kuleuven.vib.be.
15
UK-Dementia Research Institute at University College London, UK.

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.

PMID:
30630900
PMCID:
PMC6366617
DOI:
10.1126/science.aao4827
[Indexed for MEDLINE]
Free PMC Article

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