Abstract

BACE1 activity is significantly increased in the brains of Alzheimer's disease patients, potentially contributing to neurodegeneration. The voltage-gated sodium channel (Na_v1) 2-subunit (2), a type I membrane protein that covalently binds to Na_v1 -subunits, is a substrate for BACE1 and -secretase. Here, we find that BACE1–-secretase cleavages release the intracellular domain of 2, which increases mRNA and protein levels of the pore-forming Na_v1.1 -subunit in neuroblastoma cells. Similarly, endogenous 2 processing and Na_v1.1 protein levels are elevated in brains of BACE1-transgenic mice and Alzheimer's disease patients with high BACE1 levels. However, Na_v1.1 is retained inside the cells and cell surface expression of the Na_v1 -subunits and sodium current densities are markedly reduced in both neuroblastoma cells and adult hippocampal neurons from BACE1-transgenic mice. BACE1, by cleaving 2, thus regulates Na_v1 -subunit levels and controls cell-surface sodium current densities. BACE1 inhibitors may normalize membrane excitability in Alzheimer's disease patients with elevated BACE1 activity.

1. Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
2. Neural Plasticity Research Group, Department of Anaesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
3. Haldeman Laboratory of Molecular and Cellular Neurobiology, Sun Health Research Institute, Sun City, AZ 85351, USA.
4. Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, PA 19104, USA.
5. These authors contributed equally to this work.

Correspondence to: Dora M. Kovacs¹ e-mail: dora_kovacs@hms.harvard.edu

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