Research Article

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

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Science  11 Jan 2019:
Vol. 363, Issue 6423, eaao4827
DOI: 10.1126/science.aao4827

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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 GABABR1a, 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 GABABR1a'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