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

doi:10.1126/science.aao4827

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

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156 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 language	English
Article number	eaao4827
Pages (from-to)	1-7
Number of pages	7
Journal	Science
Volume	363
Issue number	6423
DOIs	https://doi.org/10.1126/science.aao4827
Publication status	Published - 11 Jan 2019

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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-β precursor protein functions as a GABABR1a ligand to modulate synaptic transmission. Science, 363(6423), 1-7. [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 N ; Remaut, Han ; Balschun, Detlef ; Wierda, Keimpe D ; Slutsky, Inna ; Farrow, Karl ; De Strooper, Bart ; de Wit, Joris. / Secreted amyloid-β precursor protein functions as a GABABR1a ligand to modulate synaptic transmission. In: Science. 2019 ; Vol. 363, No. 6423. pp. 1-7.

@article{8e0626a247f741339fa5807f006b8663,

title = "Secreted amyloid-β precursor protein functions as a GABABR1a ligand to modulate synaptic transmission",

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.",

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 = "Copyright {\textcopyright} 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.",

year = "2019",

month = jan,

day = "11",

doi = "10.1126/science.aao4827",

language = "English",

volume = "363",

pages = "1--7",

journal = "Science",

issn = "0036-8075",

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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-β precursor protein functions as a GABABR1a ligand to modulate synaptic transmission', Science, vol. 363, no. 6423, eaao4827, pp. 1-7. https://doi.org/10.1126/science.aao4827

Secreted amyloid-β precursor protein functions as a GABABR1a 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 N; 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, p. 1-7.

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

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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 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

PY - 2019/1/11

Y1 - 2019/1/11

N2 - 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.

AB - 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.

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DO - 10.1126/science.aao4827

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VL - 363

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JO - Science

JF - Science

SN - 0036-8075

IS - 6423

M1 - eaao4827

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

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