The DOI matches its Crossref record; 74 of the 74 references it cites were found in a registry or an index.
Secreted amyloid-β precursor protein functions as a GABA B R1a ligand to modulate synaptic transmission
Open accessAbstract
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
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In the citing paper
“which results in modulation of hippocampal synaptic plasticity and neurotransmission in vivo by decreasing the release of synaptic vesicles (Rice et al., 2019)”
From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Rice et al., 2019
Experimental — accuracy not yet measuredIn the citing paper
“both sAPPα and sAPPβ modulate basal synaptic transmission and short-term synaptic facilitation through binding to GABAB receptor subunit 1a at the synapse (50).”
From The β-Secretase BACE1 in Alzheimer’s Disease (2021) · cites this paper as [50]
In the citing paper
“sAPPα has been shown to act as a ligand of GABABR1a”
From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Rice et al., 2019
In the citing paper
“The function of sAPP95/sAPPη is not yet known, but a recent study showed that it binds GABABR1a, which also acts as a receptor for sAPPα and sAPPβ, resulting in a reduced probability of presynaptic release (Rice et al., 2019).”
From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Rice et al., 2019
In the citing paper
“Alternatively, the lack of MT5-MMP could prevent the formation of sAPP95/sAPPη, recently suggested to bind the GABABR1a and inhibit pre-synaptic neurotransmitter release [73].”
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Knopman, D. S., Amieva, H., Petersen, R. C., Chételat, G., Holtzman, D. M., Hyman, B. T., Nixon, R. A., & Jones, D. T. (2021) · Nature Reviews Disease Primers · doi:10.1038/s41572-021-00269-y · Cited by 2,606
The Amyloid-β Pathway in Alzheimer’s Disease
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The β-Secretase BACE1 in Alzheimer’s Disease
Hampel, H., Vassar, R., De Strooper, B., Hardy, J., Willem, M., Singh, N., Zhou, J., Yan, R., Vanmechelen, E., De Vos, A., et al. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.02.001 · Cited by 694
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Metadata
- Authors
- 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.
- Affiliations
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- Neuro-Electronics Research Flanders, Leuven, Belgium.
- KU Leuven (BE)
- Department of Physiology and Pharmacology, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
- VIB–VUB Structural Biology Research Center, Brussels, Belgium.
- Vrije Universiteit Brussel (BE)
- Tel Aviv University (IL)
- Rutgers, The State University of New Jersey (US)
- Northwestern University (US)
- VIB-VUB Center for Structural Biology (BE)
- IMEC (BE)
- VIB Center for Brain & Disease Research, Leuven, Belgium.
- ORCID
- Venue
- Science
- Published
- 2019-01-11
- Volume
- 363
- Issue
- 6423
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC6366617
- OpenAlex
- W2910128841
- Cited by
- 281
- References
- 74
- Citations by year
- 2026: 20 · 2025: 23 · 2024: 31 · 2023: 33 · 2022: 33 · 2021: 47 · 2020: 56 · 2019: 38
- FWCI
- 21.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Open Access Victoria University of Wellington | Te Herenga Waka (Figshare) (submittedVersion, cc-by-nc-nd)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Victoria University of Wellington
- Funders
- National Science Foundation (BRAIN EAGER MCB-1450895, IOS-1755189)
- National Institutes of Health (RO1AG061787)
- Robert Wood Johnson Foundation (74260)
- Alzheimer's Association (AARF-16-442885)
- European Research Council (724866, 311083)
- Fonds Wetenschappelijk Onderzoek (G094616N, G.0D76.14)
- Leuven Universiteit Fonds
- Geneeskundige Stichting Koningin Elisabeth
- KU Leuven Methusalem Grant
- Vlaams Initiatief voor Netwerken voor Dementie Onderzoek (135043)
- Stichting Voor Alzheimer Onderzoek (P#16011)
- Agency for Innovation by Science and Technology (141698)
- VUB onderzoeksfonds (SRP13)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- GABAB receptors, synaptic transmission, synaptic plasticity, synaptic vesicle release, sushi domain, GABA signaling, Alzheimer's disease, therapeutic target
- MeSH terms
- Protein Domains, Amino Acid Sequence, Animals, Cells, Cultured, Hippocampus, Humans, Male, Membrane Proteins, Mice, Inbred BALB C, Mice, Inbred C57BL, Synaptic Transmission, Neuronal Plasticity, Neurons, Peptides, Protein Binding, Receptors, GABA-A, Synapses, Synaptic Vesicles, Amyloid beta-Protein Precursor, Mice, Knockout, Proteomics, Mice, HEK293 Cells
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