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

Author

Listed:
  • 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
    Institute of Experimental Medicine, ASCR)

  • 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
    Signalling Research Centers BIOSS and CIBSS, University of Freiburg)

  • Jochen Schwenk

    (University of Freiburg
    Signalling Research Centers BIOSS and CIBSS, University of Freiburg)

  • Bernhard Bettler

    (University of Basel)

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.

Suggested Citation

  • Margarita C. Dinamarca & Adi Raveh & Andy Schneider & Thorsten Fritzius & Simon Früh & Pascal D. Rem & Michal Stawarski & Txomin Lalanne & Rostislav Turecek & Myeongjeong Choo & Valérie Besseyrias & W, 2019. "Complex formation of APP with GABAB receptors links axonal trafficking to amyloidogenic processing," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09164-3
    DOI: 10.1038/s41467-019-09164-3
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    Cited by:

    1. Chanjuan Xu & Yiwei Zhou & Yuxuan Liu & Li Lin & Peng Liu & Xiaomei Wang & Zhengyuan Xu & Jean-Philippe Pin & Philippe Rondard & Jianfeng Liu, 2024. "Specific pharmacological and Gi/o protein responses of some native GPCRs in neurons," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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