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

MC. Dinamarca, A. Raveh, A. Schneider, T. Fritzius, S. Früh, PD. Rem, M. Stawarski, T. Lalanne, R. Turecek, M. Choo, V. Besseyrias, W. Bildl, D. Bentrop, M. Staufenbiel, M. Gassmann, B. Fakler, J. Schwenk, B. Bettler,

. 2019 ; 10 (1) : 1331. [pub] 20190322

Language English Country England, Great Britain

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc19027694

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.

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$a Dinamarca, Margarita C $u Department of Biomedicine, Institute of Physiology, University of Basel, Klingelbergstr. 50/70, 4056, Basel, Switzerland.
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$a Complex formation of APP with GABAB receptors links axonal trafficking to amyloidogenic processing / $c MC. Dinamarca, A. Raveh, A. Schneider, T. Fritzius, S. Früh, PD. Rem, M. Stawarski, T. Lalanne, R. Turecek, M. Choo, V. Besseyrias, W. Bildl, D. Bentrop, M. Staufenbiel, M. Gassmann, B. Fakler, J. Schwenk, B. Bettler,
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$a 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.
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$a Raveh, Adi $u Department of Biomedicine, Institute of Physiology, University of Basel, Klingelbergstr. 50/70, 4056, Basel, Switzerland.
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$a Schneider, Andy $u Faculty of Medicine, Institute of Physiology, University of Freiburg, Hermann-Herder-Str. 7, 79104, Freiburg, Germany.
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$a Fritzius, Thorsten $u Department of Biomedicine, Institute of Physiology, University of Basel, Klingelbergstr. 50/70, 4056, Basel, Switzerland.
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$a Früh, Simon $u Department of Biomedicine, Institute of Physiology, University of Basel, Klingelbergstr. 50/70, 4056, Basel, Switzerland.
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$a Rem, Pascal D $u Department of Biomedicine, Institute of Physiology, University of Basel, Klingelbergstr. 50/70, 4056, Basel, Switzerland.
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$a Stawarski, Michal $u Department of Biomedicine, Institute of Physiology, University of Basel, Klingelbergstr. 50/70, 4056, Basel, Switzerland.
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$a Lalanne, Txomin $u Department of Biomedicine, Institute of Physiology, University of Basel, Klingelbergstr. 50/70, 4056, Basel, Switzerland.
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$a Turecek, Rostislav $u Department of Biomedicine, Institute of Physiology, University of Basel, Klingelbergstr. 50/70, 4056, Basel, Switzerland. Institute of Experimental Medicine, ASCR, Vı´denska´ 1083, 14220, Prague 4-Krc, Czech Republic.
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$a Choo, Myeongjeong $u Department of Biomedicine, Institute of Physiology, University of Basel, Klingelbergstr. 50/70, 4056, Basel, Switzerland.
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$a Besseyrias, Valérie $u Department of Biomedicine, Institute of Physiology, University of Basel, Klingelbergstr. 50/70, 4056, Basel, Switzerland.
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$a Bildl, Wolfgang $u Faculty of Medicine, Institute of Physiology, University of Freiburg, Hermann-Herder-Str. 7, 79104, Freiburg, Germany.
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$a Bentrop, Detlef $u Faculty of Medicine, Institute of Physiology, University of Freiburg, Hermann-Herder-Str. 7, 79104, Freiburg, Germany.
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$a Staufenbiel, Matthias $u Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried-Müller-Strasse 27, 72076, Tübingen, Germany.
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$a Gassmann, Martin $u Department of Biomedicine, Institute of Physiology, University of Basel, Klingelbergstr. 50/70, 4056, Basel, Switzerland.
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$a Fakler, Bernd $u Faculty of Medicine, Institute of Physiology, University of Freiburg, Hermann-Herder-Str. 7, 79104, Freiburg, Germany. Signalling Research Centers BIOSS and CIBSS, University of Freiburg, Schänzlestr. 18, 79104, Freiburg, Germany.
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$a Schwenk, Jochen $u Faculty of Medicine, Institute of Physiology, University of Freiburg, Hermann-Herder-Str. 7, 79104, Freiburg, Germany. jochen.schwenk@physiologie.uni-freiburg.de. Signalling Research Centers BIOSS and CIBSS, University of Freiburg, Schänzlestr. 18, 79104, Freiburg, Germany. jochen.schwenk@physiologie.uni-freiburg.de.
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$a Bettler, Bernhard $u Department of Biomedicine, Institute of Physiology, University of Basel, Klingelbergstr. 50/70, 4056, Basel, Switzerland. bernhard.bettler@unibas.ch.
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