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

被引：86

作者：

Dinamarca, Margarita C. ^{[1
]}

Raveh, Adi ^{[1
]}

Schneider, Andy ^{[2
]}

Fritzius, Thorsten ^{[1
]}

Frueh, Simon ^{[1
]}

Rem, Pascal D. ^{[1
]}

Stawarski, Michal ^{[1
]}

Lalanne, Txomin ^{[1
]}

Turecek, Rostislav ^{[1
,6
]}

Choo, Myeongjeong ^{[1
]}

Besseyrias, Valerie ^{[1
]}

Bildl, Wolfgang ^{[2
]}

Bentrop, Detlef ^{[2
]}

Staufenbiel, Matthias ^{[3
]}

Gassmann, Martin ^{[1
]}

Fakler, Bernd ^{[2
,4
,5
]}

Schwenk, Jochen ^{[2
,4
,5
]}

Bettler, Bernhard ^{[1
]}

机构：

[1] Univ Basel, Inst Physiol, Dept Biomed, Klingelbergstr 50-70, CH-4056 Basel, Switzerland

[2] Univ Freiburg, Fac Med, Inst Physiol, Hermann Herder Str 7, D-79104 Freiburg, Germany

[3] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Cellular Neurol, Otfried Muller Str 27, D-72076 Tubingen, Germany

[4] Univ Freiburg, Signalling Res Ctr BIOSS, Schanzlestr 18, D-79104 Freiburg, Germany

[5] Univ Freiburg, Signalling Res Ctr CIBSS, Schanzlestr 18, D-79104 Freiburg, Germany

[6] ASCR, Inst Expt Med, Videnska 1083, Prague 14220 4, Czech Republic

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

瑞士国家科学基金会;

关键词：

PRECURSOR PROTEIN; ALZHEIMERS-DISEASE; SUSHI DOMAINS; B RECEPTORS; IN-VIVO; TRANSPORT; RELEASE; PHOSPHORYLATION; IDENTIFICATION; ENDOCYTOSIS;

D O I：

10.1038/s41467-019-09164-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

GABA(B) 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 A beta, a component of senile plaques in Alzheimer's disease patients. Thus, APP/GBR complex formation links presynaptic GBR trafficking to A beta formation. Our findings support that dysfunctional axonal trafficking and reduced GBR expression in Alzheimer's disease increases A beta formation.

引用

页数：17

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