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

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.

Contribution of GABAergic interneurons to amyloid-β plaque pathology in an APP knock-in mouse model

“…Interestingly, Reelin interacts with APP [8,9,21]. GABA B R1, which functionally interacts with the APP ectodomain to regulate presynaptic inhibition [5,22] has strikingly high overlap with the relatively heterogenous population of APP-positive cells. 98% of APP-positive cells in CA1 are GABA B R1-positive ( Fig.…”

“…Therefore, we examined the co-expression of APP with γ-aminobutyric acid type B receptor subunit 1(GABA B R1) ( Fig. 1e), which functionally interacts with the APP ectodomain to regulate presynaptic inhibition [5,22] and is reported to label a neurochemically heterogeneous subset of interneurons [26]. All APP-positive cells at the SR/SLM border (100%) and in the SO (100%) are GABA B R1-positive ( Fig.…”

The organizing principle of GABAB receptor complexes: Physiological and pharmacological implications

“…A GBR antagonist disinhibits sAPP‐inhibited release, supporting that sAPP acts as GBR agonist or positive allosteric modulator. A related report shows that binding of full‐length APP to the N‐terminal sushi domain of GB1a is necessary for vesicular trafficking of GBRs to axon terminals . Consistent with vesicular GBR transport, kinesin‐1 adaptors of the c‐Jun N‐terminal kinase‐interacting protein (JIP) and calsyntenin (CSTN) protein families are shown to bind to APP and to link the APP/GBR complex to kinesin‐1 motors.…”

“…The two proteins are expected to localize to adherens junctions that mediate adhesion between pre‐ and post‐synaptic membranes . AJAP‐1 and PIANP do not play a role in vesicular axonal trafficking of GBRs . Possibly, these proteins anchor GB1a/2 receptors at synaptic sites by binding to the sushi domains in cis or in trans .…”

The Synaptic Vesicle Protein 2a Interacts With Key Pathogenic Factors in Alzheimer’s Disease: Implications for Treatment

“…2E) also validated the increase of APP in SV2A de ciency situation. It has been well documented that APP is stabilized by the GABA B receptor, at the cell surface, which leads to a reduction in APP proteolysis to Aβ [44]. Meanwhile, it has also been demonstrated that SV2A de ciency impairs its interaction with synaptotagmin 1 causing a speci c disruption of synaptic GABA release, which in turns downregulates GABA B receptor expression [45].…”