Cited by 237Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Persistent Amyloidosis following Suppression of Aβ Production in a Transgenic Model of Alzheimer Disease

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Jankowsky, Joanna L, Slunt, Hilda H, Gonzales, Victoria, Savonenko, Alena V, Wen, Jason C, Jenkins, Nancy A, Copeland, Neal G, Younkin, Linda H, Lester, Henry A, Younkin, Steven G, Borchelt, David R·2005·PLoS Medicine

DOI 10.1371/journal.pmed.0020355PMC PMC1283364

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Abstract

BACKGROUND: The proteases (secretases) that cleave amyloid-beta (Abeta) peptide from the amyloid precursor protein (APP) have been the focus of considerable investigation in the development of treatments for Alzheimer disease. The prediction has been that reducing Abeta production in the brain, even after the onset of clinical symptoms and the development of associated pathology, will facilitate the repair of damaged tissue and removal of amyloid lesions. However, no long-term studies using animal models of amyloid pathology have yet been performed to test this hypothesis. METHODS AND FINDINGS: We have generated a transgenic mouse model that genetically mimics the arrest of Abeta production expected from treatment with secretase inhibitors. These mice overexpress mutant APP from a vector that can be regulated by doxycycline. Under normal conditions, high-level expression of APP quickly induces fulminant amyloid pathology. We show that doxycycline administration inhibits transgenic APP expression by greater than 95% and reduces Abeta production to levels found in nontransgenic mice. Suppression of transgenic Abeta synthesis in this model abruptly halts the progression of amyloid pathology. However, formation and disaggregation of amyloid deposits appear to be in disequilibrium as the plaques require far longer to disperse than to assemble. Mice in which APP synthesis was suppressed for as long as 6 mo after the formation of Abeta deposits retain a considerable amyloid load, with little sign of active clearance. CONCLUSION: This study demonstrates that amyloid lesions in transgenic mice are highly stable structures in vivo that are slow to disaggregate. Our findings suggest that arresting Abeta production in patients with Alzheimer disease should halt the progression of pathology, but that early treatment may be imperative, as it appears that amyloid deposits, once formed, will require additional intervention to clear.

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Additional file 1 of Doxycycline for transgene control disrupts gut microbiome diversity without compromising acute neuroinflammatory response
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Additional file 1 of Loss of cholinergic innervation differentially affects eNOS-mediated blood flow, drainage of Aβ and cerebral amyloid angiopathy in the cortex and hippocampus of adult mice
Nizari, S., Wells, J. A., Carare, R. O., Romero, I. A., & Hawkes, C. A. (2021) · Figshare · doi:10.6084/m9.figshare.13544422
Additional file 5 of Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes
Kim, D. W., Tu, K. J., Wei, A., Lau, A., Gonzalez-Gil, A., Cao, T., Braunstein, K. E., Ling, J. P., Troncoso, J. C., Wong, P. C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26555684
Additional file 17 of Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes
Kim, D. W., Tu, K. J., Wei, A., Lau, A., Gonzalez-Gil, A., Cao, T., Braunstein, K. E., Ling, J. P., Troncoso, J. C., Wong, P. C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26555720
Additional file 9 of Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes
Kim, D. W., Tu, K. J., Wei, A., Lau, A., Gonzalez-Gil, A., Cao, T., Braunstein, K. E., Ling, J. P., Troncoso, J. C., Wong, P. C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26555696
Additional file 8 of Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes
Kim, D. W., Tu, K. J., Wei, A., Lau, A., Gonzalez-Gil, A., Cao, T., Braunstein, K. E., Ling, J. P., Troncoso, J. C., Wong, P. C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26555693
Additional file 15 of Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes
Kim, D. W., Tu, K. J., Wei, A., Lau, A., Gonzalez-Gil, A., Cao, T., Braunstein, K. E., Ling, J. P., Troncoso, J. C., Wong, P. C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26555714
Additional file 16 of Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes
Kim, D. W., Tu, K. J., Wei, A., Lau, A., Gonzalez-Gil, A., Cao, T., Braunstein, K. E., Ling, J. P., Troncoso, J. C., Wong, P. C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26555717
Additional file 1 of Altered dynamics of glymphatic flow in a mature-onset Tet-off APP mouse model of amyloidosis
Ben-Nejma, I. R. H., Keliris, A., Vanreusel, V., Ponsaerts, P., der Linden, A. V., & Keliris, G. A. (2023) · Figshare · doi:10.6084/m9.figshare.22605581
Additional file 6 of Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes
Kim, D. W., Tu, K. J., Wei, A., Lau, A., Gonzalez-Gil, A., Cao, T., Braunstein, K. E., Ling, J. P., Troncoso, J. C., Wong, P. C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26555687
Additional file 7 of Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes
Kim, D. W., Tu, K. J., Wei, A., Lau, A., Gonzalez-Gil, A., Cao, T., Braunstein, K. E., Ling, J. P., Troncoso, J. C., Wong, P. C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26555690
Additional file 11 of Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes
Kim, D. W., Tu, K. J., Wei, A., Lau, A., Gonzalez-Gil, A., Cao, T., Braunstein, K. E., Ling, J. P., Troncoso, J. C., Wong, P. C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26555702
Additional file 4 of Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes
Kim, D. W., Tu, K. J., Wei, A., Lau, A., Gonzalez-Gil, A., Cao, T., Braunstein, K. E., Ling, J. P., Troncoso, J. C., Wong, P. C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26555681
Additional file 1 of Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes
Kim, D. W., Tu, K. J., Wei, A., Lau, A., Gonzalez-Gil, A., Cao, T., Braunstein, K. E., Ling, J. P., Troncoso, J. C., Wong, P. C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26555672
Additional file 13 of Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes
Kim, D. W., Tu, K. J., Wei, A., Lau, A., Gonzalez-Gil, A., Cao, T., Braunstein, K. E., Ling, J. P., Troncoso, J. C., Wong, P. C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26555708
Additional file 2 of Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes
Kim, D. W., Tu, K. J., Wei, A., Lau, A., Gonzalez-Gil, A., Cao, T., Braunstein, K. E., Ling, J. P., Troncoso, J. C., Wong, P. C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26555675
Additional file 3 of Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes
Kim, D. W., Tu, K. J., Wei, A., Lau, A., Gonzalez-Gil, A., Cao, T., Braunstein, K. E., Ling, J. P., Troncoso, J. C., Wong, P. C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26555678
Additional file 10 of Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes
Kim, D. W., Tu, K. J., Wei, A., Lau, A., Gonzalez-Gil, A., Cao, T., Braunstein, K. E., Ling, J. P., Troncoso, J. C., Wong, P. C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26555699
Additional file 18 of Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes
Kim, D. W., Tu, K. J., Wei, A., Lau, A., Gonzalez-Gil, A., Cao, T., Braunstein, K. E., Ling, J. P., Troncoso, J. C., Wong, P. C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26555723
Additional file 12 of Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes
Kim, D. W., Tu, K. J., Wei, A., Lau, A., Gonzalez-Gil, A., Cao, T., Braunstein, K. E., Ling, J. P., Troncoso, J. C., Wong, P. C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26555705
Additional file 14 of Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes
Kim, D. W., Tu, K. J., Wei, A., Lau, A., Gonzalez-Gil, A., Cao, T., Braunstein, K. E., Ling, J. P., Troncoso, J. C., Wong, P. C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26555711
Neuronal subtype governs amyloid structure, cellular response, and cognitive outcome in genetically targeted APP mouse models
Perez, G., Lai, Z., Edwards, G. A., Dundee, J. M., Leahy, S. N., Qi, C., Qi, Y., Park, Y.-J., Lu, T., Uddin, M. D., et al. (2026) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00919-9
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Robust tauopathy and memory deficits in a mouse model constitutively overexpressing human P301L MAPT
Hamm, M. J., McNaught, K., Janus, C., Gazarov, E. A., Strickland, Z., Shubin, J., Reinhardt, J., Park, J., Rayaprolu, S., Antropov, W. V., et al. (2026) · Neurobiology of Disease · doi:10.1016/j.nbd.2026.107496
Self-citation
BindingDB Entry 50022497: Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer's disease model.
BindingDB (2025) · UC San Diego · doi:10.7270/q2xw4qks

Authors: Jankowsky, J. L., Slunt, H. H., Gonzales, V., Savonenko, A. V., Wen, J. C., Jenkins, N. A., Copeland, N. G., Younkin, L. H., Lester, H. A., Younkin, S. G., & Borchelt, D. R.
Affiliations: California Institute of Technology (US)
Johns Hopkins University (US)
National Cancer Institute (US)
Mayo Clinic (US)
Corresponding author: Jankowsky, Joanna L
Borchelt, David R
ORCID: Jankowsky, Joanna L
Savonenko, Alena V
Jenkins, Nancy A
Lester, Henry A
Borchelt, David R
Venue: PLoS Medicine
Publisher: Public Library of Science (PLoS)
Published: 2005-11-15
Volume: 2
Issue: 12
Pages: e355
ISSN: 1549-1277 (ISSN-L)
1549-1676
DOI: 10.1371/journal.pmed.0020355
PMC: PMC1283364
OpenAlex: W2152864425
Cited by: 237
References: 67
Citations by year: 2026: 3 · 2025: 6 · 2024: 23 · 2023: 10 · 2022: 14 · 2021: 7 · 2020: 5 · 2019: 9 · 2018: 9 · 2017: 14 · 2016: 19 · 2015: 9 · 2014: 13 · 2013: 8 · 2012: 16
FWCI: 6.19
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: PLoS Medicine (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
CaltechAUTHORS (California Institute of Technology) (acceptedVersion)
CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Figshare (submittedVersion, cc-by)
Funders: Alzheimer's Association
Johns Hopkins University
National Alliance for Research on Schizophrenia and Depression
Rose Hills Foundation
National Institute on Aging (K01 AG26144-01, P50 AGO5146-20, K01AG026144, P01AG015453, P50AG005146, R01AG006656)
National Cancer Institute
National Institute of Neurological Disorders and Stroke (R01NS047225)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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: Alzheimer's disease, amyloid-beta, amyloid plaques, amyloidosis, amyloid precursor protein, secretase inhibitors, transgenic mouse model, amyloid clearance
MeSH terms: Alzheimer Disease, Animals, Humans, Mice, Inbred C57BL, Mice, Transgenic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Gene Expression Profiling, Mice, Plaque, Amyloid

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Persistent Amyloidosis following Suppression of Aβ Production in a Transgenic Model of Alzheimer Disease

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