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Nat Commun. 2019 Mar 22;10(1):1331. doi: 10.1038/s41467-019-09164-3.

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

Author information

1
Department of Biomedicine, Institute of Physiology, University of Basel, Klingelbergstr. 50/70, 4056, Basel, Switzerland.
2
Faculty of Medicine, Institute of Physiology, University of Freiburg, Hermann-Herder-Str. 7, 79104, Freiburg, Germany.
3
Institute of Experimental Medicine, ASCR, Vı´denska´ 1083, 14220, Prague 4-Krc, Czech Republic.
4
Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried-Müller-Strasse 27, 72076, Tübingen, Germany.
5
Signalling Research Centers BIOSS and CIBSS, University of Freiburg, Schänzlestr. 18, 79104, Freiburg, Germany.
6
Faculty of Medicine, Institute of Physiology, University of Freiburg, Hermann-Herder-Str. 7, 79104, Freiburg, Germany. jochen.schwenk@physiologie.uni-freiburg.de.
7
Signalling Research Centers BIOSS and CIBSS, University of Freiburg, Schänzlestr. 18, 79104, Freiburg, Germany. jochen.schwenk@physiologie.uni-freiburg.de.
8
Department of Biomedicine, Institute of Physiology, University of Basel, Klingelbergstr. 50/70, 4056, Basel, Switzerland. bernhard.bettler@unibas.ch.

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.

PMID:
30902970
PMCID:
PMC6430795
DOI:
10.1038/s41467-019-09164-3
[Indexed for MEDLINE]
Free PMC Article

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