Complex Formation of APP with GABA Receptors Links Axonal Trafficking to Amyloidogenic Processing

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Mar 24

PMID 30902970

Citations 64

Authors

Margarita C Dinamarca

Adi Raveh

Andy Schneider

Thorsten Fritzius

Simon Fruh

Pascal D Rem

Michal Stawarski

Txomin Lalanne

Rostislav Turecek

Myeongjeong Choo

Valerie Besseyrias

Wolfgang Bildl

Detlef Bentrop

Matthias Staufenbiel

Martin Gassmann

Bernd Fakler

Jochen Schwenk

Bernhard Bettler

Affiliations

Soon will be listed here.

Abstract

GABA 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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