BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice
Open accessAbstract
Evidence suggests that beta-amyloid (Abeta) peptide triggers a pathogenic cascade leading to neuronal loss in Alzheimer's disease (AD). However, the causal link between Abeta and neuron death in vivo remains unclear since most animal models fail to recapitulate the dramatic cell loss observed in AD. We have recently developed transgenic mice that overexpress human APP and PS1 with five familial AD mutations (5XFAD mice) and exhibit robust neuron death. Here, we demonstrate that genetic deletion of the beta-secretase (BACE1) not only abrogates Abeta generation and blocks amyloid deposition but also prevents neuron loss found in the cerebral cortex and subiculum, brain regions manifesting the most severe amyloidosis in 5XFAD mice. Importantly, BACE1 gene deletion also rescues memory deficits in 5XFAD mice. Our findings provide strong evidence that Abeta ultimately is responsible for neuron death in AD and validate the therapeutic potential of BACE1-inhibiting approaches for the treatment of AD.
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In 5xFAD mice, stereological quantifications confirmed a significant loss of layer 5 cortical neurons at 9 and 12 months of age, which is essentially prevented upon BACE1 gene deletion.
“Stereological quantifications confirmed a significant loss of layer 5 cortical neurons at 9 and 12 months of age [47,48], which is essentially prevented upon BACE1 gene deletion [84].”
From Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models (2020) · cites this paper as [84]
In agreement with previous studies, very early onset of plaque deposition in 5XFAD mice begins around 2 months of age.
“In agreement with previous studies [20], [21], [40], we observed very early onset of plaque deposition in 5XFAD mice beginning around 2 months of age.”
From Galantamine Slows Down Plaque Formation and Behavioral Decline in the 5XFAD Mouse Model of Alzheimer’s Disease (2014) · cites this paper as [21]
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Self-citationBayer (2010) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2010.00008 · Cited by 252 · see citing works
Kandalepas, P. C., Sadleir, K. R., Eimer, W. A., Zhao, J., Nicholson, D. A., & Vassar, R. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1152-3 · Cited by 240 · see citing works
Self-citationAβ reduction in BACE1 heterozygous null 5XFAD mice is associated with transgenic APP level
Sadleir, K. R., Eimer, W. A., Cole, S. L., & Vassar, R. (2015) · Molecular Neurodegeneration · doi:10.1186/1750-1326-10-1 · Cited by 213 · see citing works
Kitazawa, M., Medeiros, R., & M. LaFerla, F. (2012) · Current Pharmaceutical Design · doi:10.2174/138161212799315786 · Cited by 178 · see citing works
Richard, B. C., Kurdakova, A., Baches, S., Bayer, T. A., Weggen, S., & Wirths, O. (2015) · Journal of Alzheimer’s Disease · doi:10.3233/jad-143120 · Cited by 142 · see citing works
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“In agreement with previous studies [20,21,40], we observed very early onset of plaque deposition in 5XFAD mice beginning around 2 months of age.”
Devi, L., & Ohno, M. (2010) · PLoS ONE · doi:10.1371/journal.pone.0012974 · Cited by 140 · see citing works
“Meanwhile, the percent alternation was indistinguishable between BACE1 and wild-type mice at 6 or 15–18 months of age, demonstrating that BACE1 mice were normal in spatial working memory function in contrast to BACE1 mice that exhibited poor spontaneous alternation performance in the Ymaze in our previous studies [7,9…”
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Self-citationGirard, S. D., Jacquet, M., Baranger, K., Migliorati, M., Escoffier, G., Bernard, A., Khrestchatisky, M., Féron, F., Rivera, S., Roman, F. S., et al. (2014) · Hippocampus · doi:10.1002/hipo.22267 · Cited by 119 · see citing works
Zhu, K., Xiang, X., Filser, S., Marinković, P., Dorostkar, M. M., Crux, S., Neumann, U., Shimshek, D. R., Rammes, G., Haass, C., et al. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.12.023 · Cited by 107 · see citing works
Flanigan, T. J., Xue, Y., Kishan Rao, S., Dhanushkodi, A., & McDonald, M. P. (2014) · Genes, Brain and Behavior · doi:10.1111/gbb.12133 · Cited by 104 · see citing works
Hitt, B. D., Jaramillo, T. C., Chetkovich, D. M., & Vassar, R. (2010) · Molecular Neurodegeneration · doi:10.1186/1750-1326-5-31 · Cited by 99 · see citing works
Self-citationFailures to reconsolidate memory in a mouse model of Alzheimer’s disease
Ohno, M. (2009) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2009.05.001 · Cited by 95 · see citing works
Self-citationSynaptic deficits in layer 5 neurons precede overt structural decay in 5xFAD mice
Buskila, Y., Crowe, S. E., & Ellis-Davies, G. C. R. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.09.016 · Cited by 77 · see citing works
Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models
Wirths, O., & Zampar, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218144 · Cited by 75 · see citing works
“Stereological quantifications confirmed a significant loss of layer 5 cortical neurons at 9 and 12 months of age [47,48], which is essentially prevented upon BACE1 gene deletion [84].”
BackgroundIncreased CSF-BACE1 activity associated with decreased hippocampus volume in Alzheimer’s disease
Ewers, M., Cheng, X., Zhong, Z., Nural, H. F., Walsh, C., Meindl, T., Teipel, S. J., Buerger, K., He, P., Shen, Y., et al. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-091153 · Cited by 58 · see citing works
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Zhao, Y., Wang, Y., Hu, J., Zhang, X., & Zhang, Y.-W. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.330209 · Cited by 28 · see citing works
Li, X., Tang, X., Zeng, J., Duan, L., Hou, Z., Li, L., Guo, Y., Chai, C., Liu, J., Wang, Y., et al. (2026) · Cell · doi:10.1016/j.cell.2025.12.020 · Cited by 21 · see citing works
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- Authors
- Ohno, M., Cole, S. L., Yasvoina, M., Zhao, J., Citron, M., Berry, R., Disterhoft, J. F., & Vassar, R.
- Affiliations
- Northwestern University (US)
- Amgen (United States) (US)
- Corresponding author
- Ohno, Masuo
- Vassar, Robert
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2007-04
- Volume
- 26
- Issue
- 1
- Pages
- 134-145
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC1876698
- OpenAlex
- W2104486619
- Cited by
- 290
- References
- 76
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 9 · 2023: 8 · 2022: 17 · 2021: 14 · 2020: 18 · 2019: 21 · 2018: 16 · 2017: 16 · 2016: 20 · 2015: 24 · 2014: 28 · 2013: 20 · 2012: 13
- FWCI
- 4.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institutes of Health (P01 AG021184, R01 AG022560, R01 MH067251, R37 AG08796)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- BACE1, beta-secretase, Alzheimer's disease, 5xFAD mice, APP/PS1 mice, amyloid-beta, neuronal loss, memory impairment, amyloid deposition, cerebral cortex, subiculum, BACE1 inhibitors, gene deletion
- MeSH terms
- Animals, Gliosis, Humans, Immunohistochemistry, Memory Disorders, Mice, Transgenic, Neurons, Immunoblotting, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Cell Death, Maze Learning, Mice, Amyloid Precursor Protein Secretases
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