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

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.

Pubmed ID: 16279840

Authors

  • Jankowsky JL
  • Slunt HH
  • Gonzales V
  • Savonenko AV
  • Wen JC
  • Jenkins NA
  • Copeland NG
  • Younkin LH
  • Lester HA
  • Younkin SG
  • Borchelt DR

Journal

PLoS medicine

Publication Data

December 20, 2005

Associated Grants

  • Agency: NIA NIH HHS, Id: K01 AG026144
  • Agency: NIA NIH HHS, Id: K01 AG026144-01
  • Agency: NIA NIH HHS, Id: K01 AG026144-02
  • Agency: NIA NIH HHS, Id: K01 AG026144-03
  • Agency: NIA NIH HHS, Id: K01 AG026144-04
  • Agency: NIA NIH HHS, Id: K01 AG026144-05
  • Agency: NIA NIH HHS, Id: K01 AG26144-01
  • Agency: NIA NIH HHS, Id: P01 AG015453
  • Agency: NIA NIH HHS, Id: P50 AGO5146-20
  • Agency: NIA NIH HHS, Id: R01 AG006656-16
  • Agency: NINDS NIH HHS, Id: R01 NS 047225

Mesh Terms

  • Alzheimer Disease
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Animals
  • Gene Expression Profiling
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Plaque, Amyloid