| First Author | Dinamarca MC | Year | 2019 |
| Journal | Nat Commun | Volume | 10 |
| Issue | 1 | Pages | 1331 |
| PubMed ID | 30902970 | Mgi Jnum | J:276486 |
| Mgi Id | MGI:6287055 | Doi | 10.1038/s41467-019-09164-3 |
| Citation | Dinamarca MC, et al. (2019) Complex formation of APP with GABAB receptors links axonal trafficking to amyloidogenic processing. Nat Commun 10(1):1331 |
| abstractText | GABAB 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 Abeta, a component of senile plaques in Alzheimer's disease patients. Thus, APP/GBR complex formation links presynaptic GBR trafficking to Abeta formation. Our findings support that dysfunctional axonal trafficking and reduced GBR expression in Alzheimer's disease increases Abeta formation. |
