. Complex formation of APP with GABAB receptors links axonal trafficking to amyloidogenic processing. Nat Commun. 2019 Mar 22;10(1):1331. PubMed.

Recommends

Please login to recommend the paper.

Comments

  1. This is a well-done study that strengthens the link between the APP ectodomain and GABA B receptor function and sheds new light on the interaction. It is exciting that both our study (Rice et al., 2019) and this of Dinamarca et al. independently validate the same domains and amino acid stretches responsible for the physical interaction between the APP ectodomain and GABABR1a. The authors also add new mechanistic insight into how full-length APP fits into the picture. Their findings indicate that full-length APP promotes axonal trafficking of GABABR1a. The interaction stabilizes both APP and GABABR1a at the cell surface and thereby suppresses BACE1-mediated cleavage of APP. Given these findings, it will be worth testing whether sAPP also affects the stabilization of GABABR on the cell surface.

    It is reasonable that both full-length APP and sAPP are binding to GABABR and have important functional consequences. This new study by Dinamarca et al. shows that full-length APP promotes axonal transport and surface stabilization of GABABR1a, and that in the absence of APP, presynaptic inhibition is impaired due to lower synaptic levels of GABABR1a. Our results showed that acute application of sAPP inhibits vesicle release through GABABR1a, also in the absence of APP. The full-length and secreted forms of APP may thus have distinct effects on the GABABR1a receptor, and this dual regulation may be part of a complex homeostatic mechanism to regulate presynaptic vesicle release. A clear difference between this study and ours is the influence of the interaction on GABABR activity. Dinamarca et al. do not observe regulation of GABABR activity by either full-length APP or sAPP as measured by G-protein activity in non-neuronal cell lines with reconstituted GABABR components. However, our study indicates that sAPP can stimulate endogenous GABABR function as measured by functional readouts in neuronal systems.

    Overall, there is now convincing evidence from multiple groups that the APP ectodomain interacts with GABABR1a and impacts presynaptic inhibition.

    References:

    . Secreted amyloid-β precursor protein functions as a GABABR1a ligand to modulate synaptic transmission. Science. 2019 Jan 11;363(6423) PubMed.

  2. The authors validate an interesting interaction between APP and GABAB1a receptor (GBR) that was recently independently identified (Rice et al., 2019). In the Rice paper in Science the functional relevance of this interaction was limited to secreted APPα. In this paper this interaction is shown to be functionally relevant for both GBR presynaptic localization and for inhibiting APP endocytosis from the plasma membrane. This physiological inhibition of APP endocytosis could have therapeutic implications since it prevents APP processing at endosomes and Aβ generation. Overall, we now have a more complete understanding of the function of the complex formation of APP with GBR.

    Additionally, we found interesting that the axonal transport of synaptic precursors containing GBR is mediated by APP binding to JIP and Kinesin. This brings back to life the physiological role of APP in axonal transport (Kamal et al., 2000). It would have been nice to analyze if knocking out APP would impair GBR receptor transport in axons.

    The data also suggests that APP functions differently in axons versus dendrites. In dendrites, despite interacting with GBR, APP does not regulate GBR dendritic localization. This polarization of APP agrees with our own findings that amyloid endocytic generation is polarized (Ubelmann et al., 2017). We found the data on APP localization at the surface being dependent on GBR binding convincing although we had hoped to see if GBR KO interfered with APP endocytosis in axons versus dendrites in addition to the data shown using HEK293 cells. There are several indications that APP trafficking in neurons is different from non-neuronal cells.

    A little less clear is the lack of impact of GABA receptor inhibitory activity on APP processing and Aβ generation, given that several other papers show that synaptic activity controls APP endocytosis and Aβ generation or secretion (Kamenetz et al., 2003; Cirrito et al., 2008; Tampellini et al., 2009, etc.).

    References:

    . Secreted amyloid-β precursor protein functions as a GABABR1a ligand to modulate synaptic transmission. Science. 2019 Jan 11;363(6423) PubMed.

    . Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I. Neuron. 2000 Nov;28(2):449-59. PubMed.

    . Bin1 and CD2AP polarise the endocytic generation of beta-amyloid. EMBO Rep. 2017 Jan;18(1):102-122. Epub 2016 Nov 28 PubMed.

    . APP processing and synaptic function. Neuron. 2003 Mar 27;37(6):925-37. PubMed.

    . Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron. 2008 Apr 10;58(1):42-51. PubMed.

    . Synaptic activity reduces intraneuronal Abeta, promotes APP transport to synapses, and protects against Abeta-related synaptic alterations. J Neurosci. 2009 Aug 5;29(31):9704-13. PubMed.

Make a Comment

To make a comment you must login or register.