Persistent amyloidosis following suppression of Aβ production in a transgenic model of Alzheimer disease

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

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Abstract

Background: The proteases (secretases) that cleave amyloid-β (Aβ) 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 Aβ 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 Aβ 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 Aβ production to levels found in nontransgenic mice. Suppression of transgenic Aβ 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 Aβ 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 Aβ 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.

Original languageEnglish (US)
Article numbere355
Pages (from-to)1318-1333
Number of pages16
JournalPLoS Medicine
Volume2
Issue number12
DOIs
StatePublished - Dec 2005

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Amyloidosis
Amyloid
Alzheimer Disease
Amyloid beta-Protein Precursor
Pathology
Amyloid Precursor Protein Secretases
Doxycycline
Amyloid Plaques
Deposits
Transgenic Mice
Serum Amyloid A Protein
Mutant Proteins
Peptide Hydrolases
Therapeutics
Animal Models
Brain
Animals
Repair
Tissue
Peptides

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Jankowsky, J. L., Slunt, H. H., Gonzales, V., Savonenko, A. V., Wen, J. C., Jenkins, N. A., ... Borchelt, D. R. (2005). Persistent amyloidosis following suppression of Aβ production in a transgenic model of Alzheimer disease. PLoS Medicine, 2(12), 1318-1333. [e355]. https://doi.org/10.1371/journal.pmed.0020355

Persistent amyloidosis following suppression of Aβ production in a transgenic model of Alzheimer disease. / 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.

In: PLoS Medicine, Vol. 2, No. 12, e355, 12.2005, p. 1318-1333.

Research output: Contribution to journalArticle

Jankowsky, JL, Slunt, HH, Gonzales, V, Savonenko, AV, Wen, JC, Jenkins, NA, Copeland, NG, Younkin, LH, Lester, HA, Younkin, SG & Borchelt, DR 2005, 'Persistent amyloidosis following suppression of Aβ production in a transgenic model of Alzheimer disease', PLoS Medicine, vol. 2, no. 12, e355, pp. 1318-1333. https://doi.org/10.1371/journal.pmed.0020355
Jankowsky JL, Slunt HH, Gonzales V, Savonenko AV, Wen JC, Jenkins NA et al. Persistent amyloidosis following suppression of Aβ production in a transgenic model of Alzheimer disease. PLoS Medicine. 2005 Dec;2(12):1318-1333. e355. https://doi.org/10.1371/journal.pmed.0020355
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. / Persistent amyloidosis following suppression of Aβ production in a transgenic model of Alzheimer disease. In: PLoS Medicine. 2005 ; Vol. 2, No. 12. pp. 1318-1333.
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