Cited by 705Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative Diseases

BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: Implications for Alzheimer’s disease therapeutics

Roberds, S. L.·2001·Human Molecular Genetics

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles in the brain. The major components of plaque, beta-amyloid peptides (Abetas), are produced from amyloid precursor protein (APP) by the activity of beta- and gamma-secretases. beta-secretase activity cleaves APP to define the N-terminus of the Abeta1-x peptides and, therefore, has been a long- sought therapeutic target for treatment of AD. The gene encoding a beta-secretase for beta-site APP cleaving enzyme (BACE) was identified recently. However, it was not known whether BACE was the primary beta-secretase in mammalian brain nor whether inhibition of beta-secretase might have effects in mammals that would preclude its utility as a therapeutic target. In the work described herein, we generated two lines of BACE knockout mice and characterized them for pathology, beta-secretase activity and Abeta production. These mice appeared to develop normally and showed no consistent phenotypic differences from their wild-type littermates, including overall normal tissue morphology and brain histochemistry, normal blood and urine chemistries, normal blood-cell composition, and no overt behavioral and neuromuscular effects. Brain and primary cortical cultures from BACE knockout mice showed no detectable beta-secretase activity, and primary cortical cultures from BACE knockout mice produced much less Abeta from APP. The findings that BACE is the primary beta-secretase activity in brain and that loss of beta-secretase activity produces no profound phenotypic defects with a concomitant reduction in beta-amyloid peptide clearly indicate that BACE is an excellent therapeutic target for treatment of AD.

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Crossref · 10.1093/hmg/10.12.1317

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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 [64]

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Authors
Roberds, S. L.
Corresponding author
Roberds, S. L.
Venue
Human Molecular Genetics
Published
2001-06-01
Volume
10
Issue
12
Pages
1317-1324
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
OpenAlex
W2155237226
Cited by
705
References
27
Citations by year
2026: 1 · 2025: 3 · 2024: 9 · 2023: 8 · 2022: 11 · 2021: 11 · 2020: 15 · 2019: 29 · 2018: 24 · 2017: 27 · 2016: 29 · 2015: 20 · 2014: 40 · 2013: 37 · 2012: 41
FWCI
22.98
Type
journal article
Language
en
Open access
closed
Locations
  • Human Molecular Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Keywords
beta-secretase, Alzheimer's disease, amyloid-beta, amyloid precursor protein, beta-secretase inhibition, therapeutic target, amyloid plaques, cortical cultures
MeSH terms
Alzheimer Disease, Animals, Brain, Cell Line, Cells, Cultured, Enzyme Inhibitors, Female, Male, Mice, Inbred CBA, Mice, Inbred C57BL, Endopeptidases, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Mice, Knockout, Culture Techniques, Mice, Amyloid Precursor Protein Secretases

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