Cited by 164Alzheimer's disease research and treatmentsEpilepsy research and treatmentNeuroscience and Neuropharmacology Research

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BACE1 Deficiency Causes Altered Neuronal Activity and Neurodegeneration

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Hu, X., Zhou, X., He, W., Yang, J., Xiong, W., Wong, P., Wilson, C. G., Yan, R.·2010·Journal of Neuroscience

DOI 10.1523/jneurosci.1334-10.2010PMC PMC2902368

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Abstract

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.

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Authors: Hu, X., Zhou, X., He, W., Yang, J., Xiong, W., Wong, P., Wilson, C. G., & Yan, R.
Affiliations: Cleveland Clinic (US)
Augusta University (US)
Johns Hopkins University (US)
ORCID: Hu, X.
Xiong, W.
Wong, P.
Wilson, C. G.
Yan, R.
Venue: Journal of Neuroscience
Publisher: Society for Neuroscience
Published: 2010-06-30
Volume: 30
Issue: 26
Pages: 8819-8829
ISSN: 0270-6474 (ISSN-L)
1529-2401
DOI: 10.1523/jneurosci.1334-10.2010
PMC: PMC2902368
OpenAlex: W2017917068
Cited by: 162
References: 55
Citations by year: 2026: 4 · 2025: 10 · 2024: 7 · 2023: 5 · 2022: 8 · 2021: 4 · 2020: 9 · 2019: 7 · 2018: 8 · 2017: 5 · 2016: 13 · 2015: 11 · 2014: 19 · 2013: 16 · 2012: 16
FWCI: 11.47
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Neuroscience (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Alzheimer's Association (AG025493)
American Health Assistance Foundation (AG025493)
Wilson Foundation
Ralph C. Wilson Foundation (AG025493)
National Institutes of Health (AG025493)
National Institute on Aging (R01AG025493, RF1AG025493, AG025493)
National Heart, Lung, and Blood Institute (R01HL081622, HL081622)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Health Sciences › Medicine › Clinical Neurology › Epilepsy research and treatment
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: BACE1, amyloid-beta, Alzheimer's disease, BACE1 inhibitors, spontaneous seizures, spike-wave discharges, kainic acid-induced seizures, fast sodium current, hippocampal neurons, neuronal hyperexcitability, epilepsy, neurodegeneration
MeSH terms: Action Potentials, Aging, Animals, Axons, Brain, Cell Membrane, Hippocampus, Kainic Acid, Membrane Potentials, Nerve Degeneration, Neurons, Phenotype, Seizures, Sodium Channels, Aspartic Acid Endopeptidases, Mice, Knockout, Mice, Amyloid Precursor Protein Secretases, In Vitro Techniques

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BACE1 Deficiency Causes Altered Neuronal Activity and Neurodegeneration

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