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

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 +3 more·2005·PLoS Medicine

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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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
Venue
PLoS Medicine
Published
2005-11-15
Volume
2
Issue
12
Pages
e355
ISSN
  • 1549-1277 (ISSN-L)
  • 1549-1676
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
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
  • 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
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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