Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-09164-3
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Funding
- EUCOMM Tools for Functional Annotation of the Mouse Genome project [FP7-HEALTH-F4-2010-261492]
- Swiss Science Foundation [31003A-172881]
- National Center for Competences in Research (NCCR) 'Synapsy, Synaptic Basis of Mental Health Disease'
- Deutsche Forschungsgemeinschaft [SFB 746]
- Czech Academy of Sciences [GACR 16-17823S]
- Swiss National Science Foundation (SNF) [31003A_172881] Funding Source: Swiss National Science Foundation (SNF)
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GABA(B) receptors (GBRs) are key regulators of synaptic release but little is known about trafficking mechanisms that control their presynaptic abundance. We now show that sequence-related epitopes in APP, AJAP-1 and PIANP bind with nanomolar affinities to the N-terminal sushi-domain of presynaptic GBRs. Of the three interacting proteins, selectively the genetic loss of APP impaired GBR-mediated presynaptic inhibition and axonal GBR expression. Proteomic and functional analyses revealed that APP associates with JIP and calsyntenin proteins that link the APP/GBR complex in cargo vesicles to the axonal trafficking motor. Complex formation with GBRs stabilizes APP at the cell surface and reduces proteolysis of APP to A beta, a component of senile plaques in Alzheimer's disease patients. Thus, APP/GBR complex formation links presynaptic GBR trafficking to A beta formation. Our findings support that dysfunctional axonal trafficking and reduced GBR expression in Alzheimer's disease increases A beta formation.
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