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BACE1 regulates voltage-gated sodium channels and neuronal activity

Abstract

BACE1 activity is significantly increased in the brains of Alzheimer's disease patients, potentially contributing to neurodegeneration. The voltage-gated sodium channel (Nav1) β2-subunit (β2), a type I membrane protein that covalently binds to Nav1 α-subunits, is a substrate for BACE1 and γ-secretase. Here, we find that BACE1–γ-secretase cleavages release the intracellular domain of β2, which increases mRNA and protein levels of the pore-forming Nav1.1 α-subunit in neuroblastoma cells. Similarly, endogenous β2 processing and Nav1.1 protein levels are elevated in brains of BACE1-transgenic mice and Alzheimer's disease patients with high BACE1 levels. However, Nav1.1 is retained inside the cells and cell surface expression of the Nav1 α-subunits and sodium current densities are markedly reduced in both neuroblastoma cells and adult hippocampal neurons from BACE1-transgenic mice. BACE1, by cleaving β2, thus regulates Nav1 α-subunit levels and controls cell-surface sodium current densities. BACE1 inhibitors may normalize membrane excitability in Alzheimer's disease patients with elevated BACE1 activity.

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Figure 1: BACE1-mediated cleavage of β2 generates β2-CTFβ and β2-ICD.
Figure 2: BACE1 regulates Nav1.1 levels.
Figure 3: DAPT treatment decreases Nav1.1 protein and mRNA levels.
Figure 4: Overexpression of recombinant β2-ICD increases Nav1.1 α-subunit levels.
Figure 5: Endogenous β2-CTF and Nav1.1 levels increase in BACE1-transgenic mouse brains.
Figure 6: BACE1 overexpression reduces sodium-current density and surface levels of Nav1 α-subunits in B104 neuroblastoma cells and hippocampal neurons.
Figure 7: Schematic representation showing BACE1-mediated regulation of Nav1.

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References

  1. Assal, F. & Cummings, J. L. Neuropsychiatric symptoms in the dementias. Curr. Opin. Neurol. 15, 445–450 (2002).

    Article  Google Scholar 

  2. Mendez, M. & Lim, G. Seizures in elderly patients with dementia: epidemiology and management. Drugs Aging 20, 791–803 (2003).

    Article  CAS  Google Scholar 

  3. Hesdorffer, D. C., Hauser, W. A., Annegers, J. F., Kokmen, E. & Rocca, W. A. Dementia and adult-onset unprovoked seizures. Neurology 46, 727–730 (1996).

    Article  CAS  Google Scholar 

  4. Hauser, W. A., Morris, M. L., Heston, L. L. & Anderson, V. E. Seizures and myoclonus in patients with Alzheimer's disease. Neurology 36, 1226–1230 (1986).

    Article  CAS  Google Scholar 

  5. Larner, A. J. & Doran, M. Clinical phenotypic heterogeneity of Alzheimer's disease associated with mutations of the presenilin-1 gene. J. Neurol. 253, 139–158 (2006).

    Article  CAS  Google Scholar 

  6. Isom, L. L. Sodium channel β subunits: anything but auxiliary. Neuroscientist 7, 42–54 (2001).

    Article  CAS  Google Scholar 

  7. Catterall, W. A. Molecular mechanisms of gating and drug block of sodium channels. Novartis Found. Symp. 241, 206–18 (2002).

    CAS  PubMed  Google Scholar 

  8. Catterall, W. A. From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron 26, 13–25 (2000).

    Article  CAS  Google Scholar 

  9. Malhotra, J. D., Kazen-Gillespie, K., Hortsch, M. & Isom, L. L. Sodium channel β subunits mediate homophilic cell adhesion and recruit ankyrin to points of cell-cell contact. J. Biol. Chem. 275, 11383–11388 (2000).

    Article  CAS  Google Scholar 

  10. Davis, T. H., Chen, C. & Isom, L. L. Sodium channel β 1 subunits promote neurite outgrowth in cerebellar granule neurons. J. Biol. Chem. 279, 51424–51432 (2004).

    Article  CAS  Google Scholar 

  11. Chen, C. et al. Reduced sodium channel density, altered voltage dependence of inactivation, and increased susceptibility to seizures in mice lacking sodium channel β 2-subunits. Proc. Natl Acad. Sci. USA 99, 17072–17077 (2002).

    Article  CAS  Google Scholar 

  12. Lopez-Santiago, L. F. et al. Sodium channel β2 subunits regulate tetrodotoxin-sensitive sodium channels in small dorsal root ganglion neurons and modulate the response to pain. J. Neurosci. 26, 7984–7994 (2006).

    Article  CAS  Google Scholar 

  13. Catterall, W. A. Molecular properties of voltage-sensitive sodium channels. Annu. Rev. Biochem. 55, 953–985 (1986).

    Article  CAS  Google Scholar 

  14. Lai, H. C. & Jan, L. Y. The distribution and targeting of neuronal voltage-gated ion channels. Nature Rev. Neurosci. 7, 548–562 (2006).

    Article  CAS  Google Scholar 

  15. Vassar, R. et al. β-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741 (1999).

    Article  CAS  Google Scholar 

  16. Sinha, S. et al. Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature 402, 537–540 (1999).

    Article  CAS  Google Scholar 

  17. Fukumoto, H., Cheung, B. S., Hyman, B. T. & Irizarry, M. C. β-Secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch. Neurol. 59, 1381–1389 (2002).

    Article  Google Scholar 

  18. Tyler, S. J., Dawbarn, D., Wilcock, G. K. & Allen, S. J. α- and β-secretase: profound changes in Alzheimer's disease. Biochem. Biophys. Res. Commun. 299, 373–376 (2002).

    Article  CAS  Google Scholar 

  19. Yang, L. B. et al. Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer's disease. Nature Med. 9, 3–4 (2003).

    Article  CAS  Google Scholar 

  20. Laird, F. M. et al. BACE1, a major determinant of selective vulnerability of the brain to amyloid-β amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J. Neurosci. 25, 11693–11709 (2005).

    Article  CAS  Google Scholar 

  21. Kitazume, S. et al. Characterization of α 2,6-sialyltransferase cleavage by Alzheimer's β -secretase (BACE1). J. Biol. Chem. 278, 14865–14871 (2003).

    Article  CAS  Google Scholar 

  22. Lichtenthaler, S. F. et al. The cell adhesion protein P-selectin glycoprotein ligand-1 is a substrate for the aspartyl protease BACE1. J. Biol. Chem. 278, 48713–48719 (2003).

    Article  CAS  Google Scholar 

  23. Willem, M. et al. Control of peripheral nerve myelination by the β-secretase BACE1. Science 314, 664–666 (2006).

    Article  CAS  Google Scholar 

  24. Kim, D. Y., Ingano, L. A., Carey, B. W., Pettingell, W. H. & Kovacs, D. M. Presenilin/γ-secretase-mediated cleavage of the voltage-gated sodium channel β2-subunit regulates cell adhesion and migration. J. Biol. Chem. 280, 23251–23261 (2005).

    Article  CAS  Google Scholar 

  25. Wong, H. K. et al. β subunits of voltage-gated sodium channels are novel substrates of β-site amyloid precursor protein-cleaving enzyme (BACE1) and γ-secretase. J. Biol. Chem. 280, 23009–23017 (2005).

    Article  CAS  Google Scholar 

  26. Koo, E. H. & Kopan, R. Potential role of presenilin-regulated signaling pathways in sporadic neurodegeneration. Nature Med. 10, S26–S33 (2004).

    Article  Google Scholar 

  27. Gong, B., Rhodes, K. J., Bekele-Arcuri, Z. & Trimmer, J. S. Type I and type II Na(+) channel α-subunit polypeptides exhibit distinct spatial and temporal patterning, and association with auxiliary subunits in rat brain. J. Comp. Neurol. 412, 342–352 (1999).

    Article  CAS  Google Scholar 

  28. Whitaker, W. R. et al. Distribution of voltage-gated sodium channel α-subunit and β-subunit mRNAs in human hippocampal formation, cortex, and cerebellum. J. Comp. Neurol. 422, 123–139 (2000).

    Article  CAS  Google Scholar 

  29. Whitaker, W. R. et al. Changes in the mRNAs encoding voltage-gated sodium channel types II and III in human epileptic hippocampus. Neuroscience 106, 275–285 (2001).

    Article  CAS  Google Scholar 

  30. Meisler, M. H., Kearney, J., Ottman, R. & Escayg, A. Identification of epilepsy genes in human and mouse. Annu. Rev. Genet. 35, 567–588 (2001).

    Article  CAS  Google Scholar 

  31. Dib-Hajj, S. D., Hinson, A. W., Black, J. A. & Waxman, S. G. Sodium channel mRNA in the B104 neuroblastoma cell line. FEBS Lett. 384, 78–82 (1996).

    Article  CAS  Google Scholar 

  32. Chang, W. P. et al. In vivo inhibition of Abeta production by memapsin 2 (β-secretase) inhibitors. J. Neurochem. 89, 1409–1416 (2004).

    Article  CAS  Google Scholar 

  33. Pertin, M. et al. Upregulation of the voltage-gated sodium channel β2 subunit in neuropathic pain models: characterization of expression in injured and non-injured primary sensory neurons. J. Neurosci. 25, 10970–10980 (2005).

    Article  CAS  Google Scholar 

  34. Lee, E. B. et al. BACE overexpression alters the subcellular processing of APP and inhibits Abeta deposition in vivo. J. Cell Biol. 168, 291–302 (2005).

    Article  CAS  Google Scholar 

  35. Schmidt, J. W. & Catterall, W. A. Biosynthesis and processing of the α subunit of the voltage-sensitive sodium channel in rat brain neurons. Cell 46, 437–444 (1986).

    Article  CAS  Google Scholar 

  36. Thomas-Crusells, J., Vieira, A., Saarma, M. & Rivera, C. A novel method for monitoring surface membrane trafficking on hippocampal acute slice preparation. J. Neurosci. Methods 125, 159–166 (2003).

    Article  CAS  Google Scholar 

  37. Zimmer, T. & Benndorf, K. The human heart and rat brain IIA Na+ channels interact with different molecular regions of the β1 subunit. J. Gen. Physiol. 120, 887–895 (2002).

    Article  CAS  Google Scholar 

  38. Zhou, J., Yi, J., Hu, N., George, A. L., Jr. & Murray, K. T. Activation of protein kinase A modulates trafficking of the human cardiac sodium channel in Xenopus oocytes. Circ. Res. 87, 33–38 (2000).

    Article  CAS  Google Scholar 

  39. Harrison, S. M. et al. BACE1 (β-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes. Mol. Cell. Neurosci. 24, 646–655 (2003).

    Article  CAS  Google Scholar 

  40. Rockenstein, E. et al. High β-secretase activity elicits neurodegeneration in transgenic mice despite reductions in amyloid-β levels: implications for the treatment of Alzheimer disease. J. Biol. Chem. 280, 32957–32967 (2005).

    Article  CAS  Google Scholar 

  41. Hu, X. et al. Bace1 modulates myelination in the central and peripheral nervous system. Nature Neurosci. 9, 1520–1525 (2006).

    Article  CAS  Google Scholar 

  42. Spampanato, J., Escayg, A., Meisler, M. H. & Goldin, A. L. Functional effects of two voltage-gated sodium channel mutations that cause generalized epilepsy with febrile seizures plus type 2. J. Neurosci. 21, 7481–7490 (2001).

    Article  CAS  Google Scholar 

  43. Claes, L. et al. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am. J. Hum. Genet. 68, 1327–1332 (2001).

    Article  CAS  Google Scholar 

  44. Mendez, M. F., Catanzaro, P., Doss, R. C., ARquello, R. & Frey, W. H., 2nd. Seizures in Alzheimer's disease: clinicopathologic study. J. Geriatr. Psychiatry. Neurol. 7, 230–233 (1994).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank S. Lichtenthaler (Ludwig-Maximilians-Universität, Germany) for the human Alzheimer's disease ADAM10 construct, H. Federoff (University of Rochester) for the nectin-1 C-terminal antibody, A. Saunders (Drexel University) for the human BACE1 construct, J. Tang (University of Oklahoma) for the dr9 inhibitor, S. Tate (GlaxoSmithKline), and C. Plumpton (GlaxoSmithKline) for sodium channel antibodies. We would also like to thank L. Isom (University of Michigan) and R. E. Tanzi (Massachusetts General Hospital) for their helpful suggestions. This work is supported by grants from the National Institutes of Health, the National Institute of Aging and the John Douglas French Alzheimer's Foundation.

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Correspondence to Dora M. Kovacs.

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Supplementary Figures S1, S2, S3, S4, S5, S6 and Supplementary Methods (PDF 664 kb)

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Kim, D., Carey, B., Wang, H. et al. BACE1 regulates voltage-gated sodium channels and neuronal activity. Nat Cell Biol 9, 755–764 (2007). https://doi.org/10.1038/ncb1602

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