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.

Department of Biomedicine Institute of Physiology University of Basel Klingelbergstr 50 70 4056 Basel Switzerland

Department of Cellular Neurology Hertie Institute for Clinical Brain Research University of Tübingen Otfried Müller Strasse 27 72076 Tübingen Germany

Faculty of Medicine Institute of Physiology University of Freiburg Hermann Herder Str 7 79104 Freiburg Germany

Institute of Experimental Medicine ASCR Vı´denska´ 1083 14220 Prague 4 Krc Czech Republic

Signalling Research Centers BIOSS and CIBSS University of Freiburg Schänzlestr 18 79104 Freiburg Germany

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