BACE1 deficiency causes altered neuronal activity and neurodegeneration

J Neurosci. 2010 Jun 30;30(26):8819-29. doi: 10.1523/JNEUROSCI.1334-10.2010.


BACE1 is required for the release of beta-amyloid (Abeta) in vivo, and inhibition of BACE1 activity is targeted for reducing Abeta generation in Alzheimer's patients. To further our understanding of the safe use of BACE1 inhibitors in human patients, we aimed to study the physiological functions of BACE1 by characterizing BACE1-null mice. Here, we report the finding of spontaneous behavioral seizures in BACE1-null mice. Electroencephalographic recordings revealed abnormal spike-wave discharges in BACE1-null mice, and kainic acid-induced seizures also occurred more frequently in BACE1-null mice compared with their wild-type littermates. Biochemical and morphological studies showed that axonal and surface levels of Na(v)1.2 were significantly elevated in BACE1-null mice, consistent with the increased fast sodium channel current recorded from BACE1-null hippocampal neurons. Patch-clamp recording also showed altered intrinsic firing properties of isolated BACE1-null hippocampal neurons. Furthermore, population spikes were significantly increased in BACE1-null brain slices, indicating hyperexcitability of BACE1-null neurons. Together, our results suggest that increased sodium channel activity contributes to the epileptic behaviors observed in BACE1-null mice. The knowledge from this study is crucial for the development of BACE1 inhibitors for Alzheimer's therapy and to the applicative study of epilepsy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology
  • Aging
  • Amyloid Precursor Protein Secretases / deficiency
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Animals
  • Aspartic Acid Endopeptidases / deficiency
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / metabolism*
  • Axons / physiology
  • Brain / physiopathology*
  • Cell Membrane / physiology
  • Hippocampus / physiopathology
  • In Vitro Techniques
  • Kainic Acid
  • Membrane Potentials / physiology
  • Mice
  • Mice, Knockout
  • Nerve Degeneration / physiopathology*
  • Neurons / physiology*
  • Phenotype
  • Seizures / chemically induced
  • Seizures / physiopathology*
  • Sodium Channels / metabolism


  • Sodium Channels
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse
  • Kainic Acid