Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A novel role for the late-onset Alzheimer’s disease (LOAD)-associated protein Bin1 in regulating postsynaptic trafficking and glutamatergic signaling

Abstract

Postsynaptic trafficking plays a key role in regulating synapse structure and function. While spiny excitatory synapses can be stable throughout adult life, their morphology and function is impaired in Alzheimer’s disease (AD). However, little is known about how AD risk genes impact synaptic function. Here we used structured superresolution illumination microscopy (SIM) to study the late-onset Alzheimer’s disease (LOAD) risk factor BIN1, and show that this protein is abundant in postsynaptic compartments, including spines. While postsynaptic Bin1 shows colocalization with clathrin, a major endocytic protein, it also colocalizes with the small GTPases Rab11 and Arf6, components of the exocytic pathway. Bin1 participates in protein complexes with Arf6 and GluA1, and manipulations of Bin1 lead to changes in spine morphology, AMPA receptor surface expression and trafficking, and AMPA receptor-mediated synaptic transmission. Our data provide new insights into the mesoscale architecture of postsynaptic trafficking compartments and their regulation by a major LOAD risk factor.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Anggono V, Huganir RL. Regulation of AMPA receptor trafficking and synaptic plasticity. Curr Opin Neurobiol. 2012;22:461–9. https://doi.org/10.1016/j.conb.2011.12.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Penzes P, Cahill ME, Jones KA, VanLeeuwen JE, Woolfrey KM. Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci. 2011;14:285–93. https://doi.org/10.1038/nn.2741.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. van der Sluijs P, Hoogenraad CC. New insights in endosomal dynamics and AMPA receptor trafficking. Semin Cell Dev Biol. 2011;22:499–505. https://doi.org/10.1016/j.semcdb.2011.06.008.

    Article  CAS  PubMed  Google Scholar 

  4. Moore FB, Baleja JD. Molecular remodeling mechanisms of the neural somatodendritic compartment. Biochim Biophys Acta. 2012;1823:1720–30. https://doi.org/10.1016/j.bbamcr.2012.06.006.

    Article  CAS  PubMed  Google Scholar 

  5. Hsu VW, Bai M, Li J. Getting active: protein sorting in endocytic recycling. Nat Rev Mol Cell Biol. 2012;13:323–8. https://doi.org/10.1038/nrm3332.

    Article  CAS  PubMed  Google Scholar 

  6. DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol. 1990;27:457–64. https://doi.org/10.1002/ana.410270502.

    Article  CAS  PubMed  Google Scholar 

  7. Bertram L, Tanzi RE. Thirty years of Alzheimer’s disease genetics: the implications of systematic meta-analyses. Nat Rev Neurosci. 2008;9:768–78. https://doi.org/10.1038/nrn2494.

    Article  CAS  PubMed  Google Scholar 

  8. Karch CM, Goate AM. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry. 2015;77:43–51. https://doi.org/10.1016/j.biopsych.2014.05.006.

    Article  CAS  PubMed  Google Scholar 

  9. Zhu JB, Tan CC, Tan L, Yu JT. State of play in Alzheimer’s disease genetics. J Alzheimers Dis. 2017;58:631–59. https://doi.org/10.3233/JAD-170062.

    Article  CAS  PubMed  Google Scholar 

  10. Tan MS, Yu JT, Tan L. Bridging integrator 1 (BIN1): form, function, and Alzheimer’s disease. Trends Mol Med. 2013;19:594–603. https://doi.org/10.1016/j.molmed.2013.06.004.

    Article  CAS  PubMed  Google Scholar 

  11. Prokic I, Cowling BS, Laporte J. Amphiphysin 2 (BIN1) in physiology and diseases. J Mol Med. 2014;92:453–63. https://doi.org/10.1007/s00109-014-1138-1.

    Article  CAS  PubMed  Google Scholar 

  12. Picas L, et al. BIN1/M-Amphiphysin2 induces clustering of phosphoinositides to recruit its downstream partner dynamin. Nat Commun. 2014;5:5647 https://doi.org/10.1038/ncomms6647.

    Article  CAS  PubMed  Google Scholar 

  13. Drager NM, et al. Bin1 directly remodels actin dynamics through its BAR domain. EMBO Rep. 2017;18:2051–66. https://doi.org/10.15252/embr.201744137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nakajo A, et al. EHBP1L1 coordinates Rab8 and Bin1 to regulate apical-directed transport in polarized epithelial cells. J Cell Biol. 2016;212:297–306. https://doi.org/10.1083/jcb.201508086.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pant S, et al. AMPH-1/Amphiphysin/Bin1 functions with RME-1/Ehd1 in endocytic recycling. Nat Cell Biol. 2009;11:1399–410. https://doi.org/10.1038/ncb1986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bayes A, et al. Characterization of the proteome, diseases and evolution of the human postsynaptic density. Nat Neurosci. 2011;14:19–21. https://doi.org/10.1038/nn.2719.

    Article  CAS  PubMed  Google Scholar 

  17. Grossmann, AH et al. The small GTPase ARF6 regulates protein trafficking to control cellular function during development and in disease. Small GTPases. https://doi.org/10.1080/21541248.2016.1259710 (2016).

  18. Hongu T, Kanaho Y. Activation machinery of the small GTPase Arf6. Adv Biol Regul. 2014;54:59–66. https://doi.org/10.1016/j.jbior.2013.09.014.

    Article  CAS  PubMed  Google Scholar 

  19. Johnson DL, Wayt J, Wilson JM, Donaldson JG. Arf6 and Rab22 mediate T cell conjugate formation by regulating clathrin-independent endosomal membrane trafficking. J Cell Sci. 2017;130:2405–15. https://doi.org/10.1242/jcs.200477.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Harris, KM & Weinberg, RJ Ultrastructure of synapses in the mammalian brain. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a005587 (2012).

  21. Dhar SS, Liang HL, Wong-Riley MT. Nuclear respiratory factor 1 co-regulates AMPA glutamate receptor subunit 2 and cytochrome c oxidase: tight coupling of glutamatergic transmission and energy metabolism in neurons. J Neurochem. 2009;108:1595–606. https://doi.org/10.1111/j.1471-4159.2009.05929.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Caplan S, et al. A tubular EHD1-containing compartment involved in the recycling of major histocompatibility complex class I molecules to the plasma membrane. EMBO J. 2002;21:2557–67. https://doi.org/10.1093/emboj/21.11.2557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Posey AD Jr., et al. EHD1 mediates vesicle trafficking required for normal muscle growth and transverse tubule development. Dev Biol. 2014;387:179–90. 10.1016/j.ydbio.2014.01.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Oku Y, Huganir RL. AGAP3 and Arf6 regulate trafficking of AMPA receptors and synaptic plasticity. J Neurosci. 2013;33:12586–98. https://doi.org/10.1523/JNEUROSCI.0341-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Scholz R, et al. AMPA receptor signaling through BRAG2 and Arf6 critical for long-term synaptic depression. Neuron. 2010;66:768–80. https://doi.org/10.1016/j.neuron.2010.05.003.

    Article  CAS  PubMed  Google Scholar 

  26. Penzes P, Vanleeuwen JE. Impaired regulation of synaptic actin cytoskeleton in Alzheimer’s disease. Brain Res Rev. 2011;67:184–92. https://doi.org/10.1016/j.brainresrev.2011.01.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Karch CM, Cruchaga C, Goate AM. Alzheimer’s disease genetics: from the bench to the clinic. Neuron. 2014;83:11–26. https://doi.org/10.1016/j.neuron.2014.05.041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Glennon EB, et al. BIN1 is decreased in sporadic but not familial Alzheimer’s disease or in aging. PLoS One. 2013;8:e78806 https://doi.org/10.1371/journal.pone.0078806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Adams SL, Tilton K, Kozubek JA, Seshadri S, Delalle I. Subcellular changes in bridging integrator 1 protein expression in the cerebral cortex during the progression of Alzheimer disease pathology. J Neuropathol Exp Neurol. 2016;75:779–90. https://doi.org/10.1093/jnen/nlw056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Holler CJ, et al. Bridging integrator 1 (BIN1) protein expression increases in the Alzheimer’s disease brain and correlates with neurofibrillary tangle pathology. J Alzheimers Dis. 2014;42:1221–7. https://doi.org/10.3233/JAD-132450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lee E, et al. Amphiphysin 2 (Bin1) and T-tubule biogenesis in muscle. Science. 2002;297:1193–6. https://doi.org/10.1126/science.1071362.

    Article  CAS  PubMed  Google Scholar 

  32. Copits BA, Swanson GT. Kainate receptor post-translational modifications differentially regulate association with 4.1N to control activity-dependent receptor endocytosis. J Biol Chem. 2013;288:8952–65. https://doi.org/10.1074/jbc.M112.440719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Smith KR, et al. Psychiatric risk factor ANK3/ankyrin-G nanodomains regulate the structure and function of glutamatergic synapses. Neuron. 2014;84:399–415. https://doi.org/10.1016/j.neuron.2014.10.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Burette AC, et al. Organization of TNIK in dendritic spines. J Comp Neurol. 2015;523:1913–24. https://doi.org/10.1002/cne.23770.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kopec CD, Li B, Wei W, Boehm J, Malinow R. Glutamate receptor exocytosis and spine enlargement during chemically induced long-term potentiation. J Neurosci. 2006;26:2000–9. https://doi.org/10.1523/JNEUROSCI.3918-05.2006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by: R01s MH097216, MH107182, and MH097216 and R56 AG063433 to PP, German Research Foundation (DFG) Postdoctoral Research Fellowship SCHU2710/1-1 to BS, NS064091 MM, and NS039444 to RJW. Imaging work was partly performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Structured illumination microscopy was performed on a Nikon N-SIM system, purchased through the support of NIH 1S10OD016342-01. We thank Joshua Rappoport, Constadina Arvanitis, and Teng Leong Chew for assistance with imaging and analysis. All experiments involving animals were performed according to the Institutional Animal Care and Use Committee of NU.

Author information

Authors and Affiliations

Authors

Contributions

BS performed and analyzed confocal and SIM imaging experiments, some biochemistry, led the project and wrote the paper. DPB performed FRAP experiments, Arf6 activation assays, GluA1 surface expression experiments, PLA experiments, some biochemistry, data analysis and manuscript writing. KJK performed some SIM imaging. SY performed Bin1 developmental expression experiments. KM performed GluA1 surface expression experiments and FRAP experiments. KH provided general help for all experiments. CJK performed electrophysiology experiments. MDMS, MF, KRS performed biochemistry experiments. JMFP and RG performed molecular biology. MM supervised electrophysiology and advised on the project. ACB performed electron microscopy experiments. JR assisted with SIM imaging studies and data analysis. RJW supervised the electron microscopy experiments. PP supervised the project and wrote the paper.

Corresponding author

Correspondence to Peter Penzes.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schürmann, B., Bermingham, D.P., Kopeikina, K.J. et al. A novel role for the late-onset Alzheimer’s disease (LOAD)-associated protein Bin1 in regulating postsynaptic trafficking and glutamatergic signaling. Mol Psychiatry 25, 2000–2016 (2020). https://doi.org/10.1038/s41380-019-0407-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-019-0407-3

This article is cited by

Search

Quick links