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 N. Savas; Han Remaut; Detlef Balschun; Keimpe D. Wierda; Inna Slutsky; Karl Farrow; Bart De Strooper; Joris De Wit

doi:10.1126/science.aao4827

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 N. 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 journal › Article › peer-review

227 Scopus citations

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 language	English
Article number	eaao4827
Journal	Science
Volume	363
Issue number	6423
DOIs	https://doi.org/10.1126/science.aao4827
State	Published - 11 Jan 2019

Funding

Funders	Funder number
European Commission
National Science Foundation	1755189
Horizon 2020 Framework Programme	311083
National Institute on Aging	R01AG061787
H2020 European Research Council	724866, G.0946.16N
Robert Wood Johnson Foundation	RO1AG061787

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1126/science.aao4827

Cite this

Rice, H. C., De Malmazet, D., Schreurs, A., Frere, S., Van Molle, I., Volkov, A. N., Creemers, E., Vertkin, I., Nys, J., Ranaivoson, F. M., Comoletti, D., Savas, J. N., Remaut, H., Balschun, D., Wierda, K. D., 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, 363(6423), Article eaao4827. https://doi.org/10.1126/science.aao4827

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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{\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 = "Publisher Copyright: {\textcopyright} 2017 The Authors.",

year = "2019",

month = jan,

day = "11",

doi = "10.1126/science.aao4827",

language = "אנגלית",

volume = "363",

journal = "Science",

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

Research output: Contribution to journal › Article › peer-review

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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 N.

AU - Remaut, Han

AU - Balschun, Detlef

AU - Wierda, Keimpe D.

AU - Slutsky, Inna

AU - Farrow, Karl

AU - De Strooper, Bart

AU - De Wit, Joris

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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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