Secreted amyloid-b precursor protein functions as a GABA B R1a 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 Nicholas Savas, Han Remaut, Detlef Balschun, Keimpe D. Wierda, Inna Slutsky, Karl Farrow, Bart De Strooper*, Joris De Wit

*Corresponding author for this work

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Amyloid-b 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 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.

Original languageEnglish (US)
Article numbereaao4827
JournalScience
Volume363
Issue number6423
DOIs
StatePublished - Jan 11 2019

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Aminobutyrates
Amyloid beta-Protein Precursor
Synaptic Transmission
gamma-Aminobutyric Acid
Ligands
Neurotransmitter Receptor
Synaptic Vesicles
Synapses
Hippocampus
Alzheimer Disease
Peptides
Acids

ASJC Scopus subject areas

  • General

Cite this

Rice, H. C., De Malmazet, D., Schreurs, A., Frere, S., Van Molle, I., Volkov, A. N., ... De Wit, J. (2019). Secreted amyloid-b precursor protein functions as a GABA B R1a ligand to modulate synaptic transmission Science, 363(6423), [eaao4827]. https://doi.org/10.1126/science.aao4827
Rice, Heather C. ; De Malmazet, Daniel ; Schreurs, An ; Frere, Samuel ; Van Molle, Inge ; Volkov, Alexander N. ; Creemers, Eline ; Vertkin, Irena ; Nys, Julie ; Ranaivoson, Fanomezana M. ; Comoletti, Davide ; Savas, Jeffrey Nicholas ; Remaut, Han ; Balschun, Detlef ; Wierda, Keimpe D. ; Slutsky, Inna ; Farrow, Karl ; De Strooper, Bart ; De Wit, Joris. / Secreted amyloid-b precursor protein functions as a GABA B R1a ligand to modulate synaptic transmission In: Science. 2019 ; Vol. 363, No. 6423.
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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’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 Nicholas} and Han Remaut and Detlef Balschun and Wierda, {Keimpe D.} and Inna Slutsky and Karl Farrow and {De Strooper}, Bart and {De Wit}, Joris",
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Rice, HC, De Malmazet, D, Schreurs, A, Frere, S, Van Molle, I, Volkov, AN, Creemers, E, Vertkin, I, Nys, J, Ranaivoson, FM, Comoletti, D, Savas, JN, Remaut, H, Balschun, D, Wierda, KD, Slutsky, I, Farrow, K, De Strooper, B & De Wit, J 2019, ' Secreted amyloid-b precursor protein functions as a GABA B R1a ligand to modulate synaptic transmission ', Science, vol. 363, no. 6423, eaao4827. https://doi.org/10.1126/science.aao4827

Secreted amyloid-b precursor protein functions as a GABA B R1a ligand to modulate synaptic transmission . / Rice, Heather C.; De Malmazet, Daniel; Schreurs, An; Frere, Samuel; Van Molle, Inge; Volkov, Alexander N.; Creemers, Eline; Vertkin, Irena; Nys, Julie; Ranaivoson, Fanomezana M.; Comoletti, Davide; Savas, Jeffrey Nicholas; Remaut, Han; Balschun, Detlef; Wierda, Keimpe D.; Slutsky, Inna; Farrow, Karl; De Strooper, Bart; De Wit, Joris.

In: Science, Vol. 363, No. 6423, eaao4827, 11.01.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Secreted amyloid-b precursor protein functions as a GABA B R1a ligand to modulate synaptic transmission

AU - Rice, Heather C.

AU - De Malmazet, Daniel

AU - Schreurs, An

AU - Frere, Samuel

AU - Van Molle, Inge

AU - Volkov, Alexander N.

AU - Creemers, Eline

AU - Vertkin, Irena

AU - Nys, Julie

AU - Ranaivoson, Fanomezana M.

AU - Comoletti, Davide

AU - Savas, Jeffrey Nicholas

AU - Remaut, Han

AU - Balschun, Detlef

AU - Wierda, Keimpe D.

AU - Slutsky, Inna

AU - Farrow, Karl

AU - De Strooper, Bart

AU - De Wit, Joris

PY - 2019/1/11

Y1 - 2019/1/11

N2 - Amyloid-b 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 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.

AB - Amyloid-b 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 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.

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U2 - 10.1126/science.aao4827

DO - 10.1126/science.aao4827

M3 - Article

VL - 363

JO - Science

JF - Science

SN - 0036-8075

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Rice HC, De Malmazet D, Schreurs A, Frere S, Van Molle I, Volkov AN et al. Secreted amyloid-b precursor protein functions as a GABA B R1a ligand to modulate synaptic transmission Science. 2019 Jan 11;363(6423). eaao4827. https://doi.org/10.1126/science.aao4827