BACE1 (β-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes
Abstract
BACE1 is a key enzyme in the generation of Abeta, the major component of senile plaques in the brains of Alzheimer's disease patients. We have generated transgenic mice expressing human BACE1 with the Cam Kinase II promoter driving neuronal-specific expression. The transgene contains the full-length coding sequence of human BACE1 preceding an internal ribosome entry site element followed by a LacZ reporter gene. These animals exhibit a bold, exploratory behavior and show elevated 5-hydroxytryptamine turnover. We have also generated a knockout mouse in which LacZ replaces the first exon of murine BACE1. Interestingly these animals show a contrasting behavior, being timid and less exploratory. Despite these clear differences both mouse lines are viable and fertile with no changes in morbidity. These results suggest an unexpected role for BACE1 in neurotransmission, perhaps through changes in amyloid precursor protein processing and Abeta levels.
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Many BACE1 knockout mouse phenotypes, such as peripheral hypomyelination and synaptic deficits, result from loss of function of substrates that depend on BACE1 activation.
“Many of the BACE1 KO mouse phenotypes, such as the peripheral hypomyelination and synaptic deficits, are due to loss of function of substrates depending on the activation by BACE1.”
From The β-Secretase BACE1 in Alzheimer’s Disease (2021) · cites this paper as [43]
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- Authors
- Harrison, S. M., Harper, A. J., Hawkins, J., Duddy, G., Grau, E., Pugh, P. L., Winter, P. H., Shilliam, C. S., Hughes, Z. A., Dawson, L. A., Gonzalez, M. I., Upton, N., Pangalos, M. N., & Dingwall, C.
- Affiliations
- GlaxoSmithKline (United Kingdom) (GB)
- Wellcome Sanger Institute (GB)
- Corresponding author
- Dingwall, Colin
- Venue
- Molecular and Cellular Neuroscience
- Publisher
- Elsevier BV
- Published
- 2003-11
- Volume
- 24
- Issue
- 3
- Pages
- 646-655
- ISSN
- 1044-7431 (ISSN-L)
- OpenAlex
- W1989472405
- Cited by
- 152
- References
- 51
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 6 · 2023: 1 · 2022: 3 · 2021: 5 · 2020: 1 · 2019: 7 · 2018: 3 · 2017: 5 · 2016: 8 · 2015: 7 · 2014: 13 · 2013: 6 · 2012: 14
- FWCI
- 4.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular and Cellular Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- BACE1, beta-secretase, Alzheimer's disease, amyloid-beta, APP processing, transgenic mice, knockout mice, serotonin turnover, serotonin, exploratory behavior, neurotransmission
- MeSH terms
- Alzheimer Disease, Animals, Behavior, Animal, Brain, Cells, Cultured, Disease Models, Animal, Exploratory Behavior, Fear, Mice, Transgenic, Synaptic Transmission, Endopeptidases, Phenotype, Serotonin, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Genes, Reporter, Mice, Knockout, Transgenes, Mice, Amyloid Precursor Protein Secretases
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