BACE1 deficiency causes altered neuronal activity and neurodegeneration

Xiangyou Hu, Xiangdong Zhou, Wanxia He, Jun Yang, Wencheng Xiong, Philip Wong, Christopher G. Wilson, Riqiang Yan

Research output: Contribution to journalArticlepeer-review

117 Scopus citations

Abstract

BACE1 is required for the release of β-amyloid (Aβ) in vivo, and inhibition of BACE1 activity is targeted for reducing Aβ 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 acidinduced 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 Nav1.2 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.

Original languageEnglish (US)
Pages (from-to)8819-8829
Number of pages11
JournalJournal of Neuroscience
Volume30
Issue number26
DOIs
StatePublished - Jun 30 2010

ASJC Scopus subject areas

  • Neuroscience(all)

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