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Download fileSecreted amyloid-b precursor protein functions as a GABA B R1a ligand to modulate synaptic transmission
journal contribution
posted on 04.08.2022, 22:23 authored by HC Rice, D De Malmazet, A Schreurs, S Frere, I Van Molle, AN Volkov, E Creemers, I Vertkin, J Nys, FM Ranaivoson, Davide ComolettiDavide Comoletti, JN Savas, H Remaut, D Balschun, KD Wierda, I Slutsky, K Farrow, B De Strooper, J De WitAmyloid-b 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 g-aminobutyric acid type B receptor subunit 1a (GABA B R1a). sAPP-GABA B R1a 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 GABA B R1a binding region within APP suppressed in vivo spontaneous neuronal activity in the hippocampus of anesthetized Thy1-GCaMP6s mice. Our findings identify GABA B R1a as a synaptic receptor for sAPP and reveal a physiological role for sAPP in regulating GABA B R1a function to modulate synaptic transmission.
Funding
Collaborative Research: Structure and Function of Reelin in Brain Development | Funder: RUTGERS UNIVERSITY | Grant ID: 1755189
History
Preferred citation
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. (2019). Secreted amyloid-b precursor protein functions as a GABA B R1a ligand to modulate synaptic transmission. Science, 363(6423), 143-143. https://doi.org/10.1126/science.aao4827Publisher DOI
Journal title
ScienceVolume
363Issue
6423Publication date
11/01/2019Pagination
143-143Publisher
American Association for the Advancement of Science (AAAS)Publication status
PublishedISSN
0036-8075eISSN
1095-9203Article number
ARTN eaao4827Language
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Categories
Keywords
BiomedicalBasic ScienceAgingNeurosciencesDementiaNeurodegenerativeAlzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD)Alzheimer's DiseaseBrain DisordersAcquired Cognitive ImpairmentNeurological2.1 Biological and endogenous factorsAmino Acid SequenceAmyloid beta-Protein PrecursorAnimalsCells, CulturedHEK293 CellsHippocampusHumansMaleMembrane ProteinsMiceMice, Inbred BALB CMice, Inbred C57BLMice, KnockoutNeuronal PlasticityNeuronsPeptidesProtein BindingProtein DomainsProteomicsReceptors, GABA-ASynapsesSynaptic TransmissionSynaptic Vesicles1 Underpinning research1.1 Normal biological development and functioning2 AetiologyScience & TechnologyMultidisciplinary SciencesScience & Technology - Other TopicsLONG-TERM POTENTIATIONPHYSIOLOGICAL FUNCTIONSPRESYNAPTIC INHIBITIONRECEPTOR ANTAGONISTMOLECULAR-STRUCTURENEURONAL-ACTIVITYMICE LACKINGAPPS-ALPHAREVEALSRELEASEGeneral Science & Technology