title: Persistent amyloidosis following suppression of Abeta production in a transgenic model of Alzheimer disease.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. jlj2@caltech.edu
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Jankowsky
authors.forename: Hilda H
authors.initials: HH
authors.lastname: Slunt
authors.forename: Victoria
authors.initials: V
authors.lastname: Gonzales
authors.forename: Alena V
authors.initials: AV
authors.lastname: Savonenko
authors.forename: Jason C
authors.initials: JC
authors.lastname: Wen
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.forename: Linda H
authors.initials: LH
authors.lastname: Younkin
authors.forename: Henry A
authors.initials: HA
authors.lastname: Lester
authors.forename: Steven G
authors.initials: SG
authors.lastname: Younkin
authors.forename: David R
authors.initials: DR
authors.lastname: Borchelt
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058225:Plaque, Amyloid
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor