Rice, HC; de Malmazet, D; Schreurs, A; Frere, S; Van Molle, I; Volkov, AN; Creemers, E; ... de Wit, J; + view all 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; - view fewer (2019) Secreted amyloid-β precursor protein functions as a GABABR1a ligand to modulate synaptic transmission. Science , 363 (6423) 10.1126/science.aao4827.

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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.

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