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

Research output: Contribution to journal › Article

82 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, 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 {\circledC} 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 = "1",

day = "11",

doi = "10.1126/science.aao4827",

language = "English",

volume = "363",

pages = "1--7",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of 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-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

TY - JOUR

T1 - Secreted amyloid-β precursor protein functions as a GABABR1a 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 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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U2 - 10.1126/science.aao4827

DO - 10.1126/science.aao4827

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VL - 363

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EP - 7

JO - Science

JF - Science

SN - 0036-8075

IS - 6423

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