title: Modulation of amyloid precursor protein expression reduces β-amyloid deposition in a mouse model.
abstract: OBJECTIVE
  Proteolytic cleavage of the amyloid precursor protein (APP) generates β-amyloid (Aβ) peptides. Prolonged accumulation of Aβ in the brain underlies the pathogenesis of Alzheimer disease (AD) and is regarded as a principal target for development of disease-modifying therapeutics.
  
  
  METHODS
  Using Chinese hamster ovary (CHO) APP751SW cells, we identified and characterized effects of 2-([pyridine-2-ylmethyl]-amino)-phenol (2-PMAP) on APP steady-state level and Aβ production. Outcomes of 2-PMAP treatment on Aβ accumulation and associated memory deficit were studied in APPSW /PS1dE9 AD transgenic model mice.
  
  
  RESULTS
  In CHO APP751SW cells, 2-PMAP lowered the steady-state APP level and inhibited Aβx-40 and Aβx-42 production in a dose-response manner with a minimum effective concentration ≤ 0.5μM. The inhibitory effect of 2-PMAP on translational efficiency of APP mRNA into protein was directly confirmed using a 35S-methionine/cysteine metabolic labeling technique, whereas APP mRNA level remained unaltered. Administration of 2-PMAP to APPSW /PS1dE9 mice reduced brain levels of full-length APP and its C-terminal fragments and lowered levels of soluble Aβx-40 and Aβx-42 . Four-month chronic treatment of APPSW /PS1dE9 mice revealed no observable toxicity and improved animals' memory performance. 2-PMAP treatment also caused significant reduction in brain Aβ deposition determined by both unbiased quantification of Aβ plaque load and biochemical analysis of formic acid-extracted Aβx-40 and Aβx-42 levels and the level of oligomeric Aβ.
  
  
  CONCLUSIONS
  We demonstrate the potential of modulating APP steady-state expression level as a safe and effective approach for reducing Aβ deposition in AD transgenic model mice.
authors.affiliation: Department of Neurology, New York University School of Medicine, New York, NY.
authors.forename: Ayodeji A
authors.initials: AA
authors.lastname: Asuni
authors.forename: Maitea
authors.initials: M
authors.lastname: Guridi
authors.forename: Joanna E
authors.initials: JE
authors.lastname: Pankiewicz
authors.forename: Sandrine
authors.initials: S
authors.lastname: Sanchez
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Sadowski
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1