Complex formation of APP with GABAB receptors links axonal trafficking to amyloidogenic processing

Margarita C. Dinamarca, Adi Raveh, Andy Schneider, Thorsten Fritzius, Simon Früh, Pascal D. Rem, Michal Stawarski, Txomin Lalanne, Rostislav Turecek, Myeongjeong Choo, Valérie Besseyrias, Wolfgang Bildl, Detlef Bentrop, Matthias Staufenbiel, Martin Gassmann, Bernd Fakler, Jochen Schwenk () and Bernhard Bettler ()
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Margarita C. Dinamarca: University of Basel
Adi Raveh: University of Basel
Andy Schneider: University of Freiburg
Thorsten Fritzius: University of Basel
Simon Früh: University of Basel
Pascal D. Rem: University of Basel
Michal Stawarski: University of Basel
Txomin Lalanne: University of Basel
Rostislav Turecek: University of Basel
Myeongjeong Choo: University of Basel
Valérie Besseyrias: University of Basel
Wolfgang Bildl: University of Freiburg
Detlef Bentrop: University of Freiburg
Matthias Staufenbiel: University of Tübingen
Martin Gassmann: University of Basel
Bernd Fakler: University of Freiburg
Jochen Schwenk: University of Freiburg
Bernhard Bettler: University of Basel

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract 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 Aβ, a component of senile plaques in Alzheimer’s disease patients. Thus, APP/GBR complex formation links presynaptic GBR trafficking to Aβ formation. Our findings support that dysfunctional axonal trafficking and reduced GBR expression in Alzheimer’s disease increases Aβ formation.

Date: 2019
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DOI: 10.1038/s41467-019-09164-3

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