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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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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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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DOI: https://doi.org/10.1038/ncb1602
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