BACE1-/- mice exhibit seizure activity that does not correlate with sodium channel level or axonal localization
Open accessAbstract
Background: BACE1 is a key enzyme in the generation of the Aβ peptide that plays a central role in the pathogenesis of Alzheimer's disease. While BACE1 is an attractive therapeutic target, its normal physiological function remains largely unknown. Examination of BACE1-/- mice can provide insight into this function and also help anticipate consequences of BACE1 inhibition. Here we report a seizure-susceptibility phenotype that we have identified and characterized in BACE1-/- mice. Results: We find that electroencephalographic recordings reveal epileptiform abnormalities in some BACE1-/- mice, occasionally including generalized tonic-clonic and absence seizures. In addition, we find that kainic acid injection induces seizures of greater severity in BACE1-/- mice relative to BACE1+/+ littermates, and causes excitotoxic cell death in a subset of BACE1-/- mice. This hyperexcitability phenotype is variable and appears to be manifest in approximately 30% of BACE1-/- mice. Finally, examination of the expression and localization of the voltage-gated sodium channel α-subunit Na v 1.2 reveals no correlation with BACE1 genotype or any measure of seizure susceptibility. Conclusions: Our data indicate that BACE1 deficiency predisposes mice to spontaneous and pharmacologically-induced seizure activity. This finding has implications for the development of safe therapeutic strategies for reducing Aβ levels in Alzheimer's disease. Further, we demonstrate that altered sodium channel expression and axonal localization are insufficient to account for the observed effect, warranting investigation of alternative mechanisms.
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BACE1 KO mice exhibit a variety of neurological defects.
“In addition, BACE1 KO mice exhibit a variety of neurological defects [641–643]”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [642]
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- Authors
- Hitt, B. D., Jaramillo, T. C., Chetkovich, D. M., & Vassar, R.
- Affiliations
- Northwestern University (US)
- Corresponding author
- Vassar, Robert
- Venue
- Molecular Neurodegeneration
- Published
- 2010-08-23
- Volume
- 5
- Issue
- 1
- Pages
- 31-31
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC2933677
- OpenAlex
- W2153669928
- Cited by
- 99
- References
- 59
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 5 · 2022: 6 · 2021: 2 · 2020: 5 · 2019: 6 · 2018: 6 · 2017: 6 · 2016: 8 · 2015: 6 · 2014: 13 · 2013: 13 · 2012: 6
- FWCI
- 6.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Northwestern University
- National Institutes of Health (5 -T32, NIH T32)
- National Institute on Aging (RF1AG022560)
- National Institute of General Medical Sciences (T32GM008061)
- National Institute of Neurological Disorders and Stroke (K02NS055995, R21NS065391, R01NS059934)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- BACE1, seizure susceptibility, epilepsy, epileptiform abnormalities, kainic acid-induced seizures, excitotoxic cell death, axonal localization, amyloid-beta, Alzheimer's disease
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