BACE1 deficiency causes altered neuronal activity and neurodegeneration.
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.
Hu
Xiangyou
X
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Zhou
Xiangdong
X
He
Wanxia
W
Yang
Jun
J
Xiong
Wencheng
W
Wong
Philip
P
Wilson
Christopher G
CG
Yan
Riqiang
R
D000200:Action Potentials / Q000502:physiology; D000375:Aging; D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001369:Axons / Q000502:physiology; D001921:Brain / Q000503:physiopathology*; D002462:Cell Membrane / Q000502:physiology; D006624:Hippocampus / Q000503:physiopathology; D066298:In Vitro Techniques; D007608:Kainic Acid; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000503:physiopathology*; D009474:Neurons / Q000502:physiology*; D010641:Phenotype; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*; D015222:Sodium Channels / Q000378:metabolism
D015222:Sodium Channels; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D007608:Kainic Acid