期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-09164-3
关键词
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资金
- 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)
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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