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

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

11 janv. 2019Science

Auteurs

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

Résumé

A physiological function for sAPP?

Although the pathological role of the amyloid-β precursor protein (APP) in Alzheimer's disease is well studied, the physiological role of this protein has remained elusive. Rice et al. found that the secreted ectodomain of APP (sAPP) binds to GABA B R1a, the metabotropic receptor for the inhibitory neurotransmitter γ-aminobutyric acid (GABA) (see the Perspective by Korte). Binding suppressed synaptic vesicle release and modulated synaptic transmission and plasticity in mice. A short, 17–amino acid peptide in APP bound to GABA B R1a's sushi 1 domain, conferring structure to this unstructured domain. Therapeutics targeting this interaction could potentially benefit a range of neurological disorders in which GABA signaling is implicated.

Science , this issue p. eaao4827 ; see also p. 123