title: Prolonged In Vivo Retention of a Cathepsin D Targeted Optical Contrast Agent in a Mouse Model of Alzheimer's Disease.
abstract: BACKGROUND
  Cathepsin D (CatD) is a lysosomal protease that is elevated early in Alzheimer's disease (AD). We have previously developed a Targeted contrast agent (CA) to detect CatD activity in vivo, consisting of a magnetic resonance imaging/fluorescent moiety linked to a cell penetrating peptide (CPP) by means of a CatD cleavage site and have demonstrated its uptake in the brain of an AD mouse model.
  
  
  OBJECTIVE
  The purpose of this study was to characterize the in vivo retention of a near infra-red fluorescent dye labeled version of this CA.
  
  
  METHODS
  Six adult C57Bl/6 wild-type mice and six adult 5XFAD transgenic AD mice were studied using a small animal imaging system at five and twelve months of age using our novel Targeted CA, or two different control CAs; a Non-Targeted (lacking the CatD cleavage site) and a Non-Penetrating (lacking the CPP). Following intravenous CA administration, the optical signal was recorded within the brain and uptake and washout curves were measured and fitted to a one-phase exponential decay curve.
  
  
  RESULTS
  In all wild-type and 5XFAD mice, the washout of the Targeted CA that included a CPP domain was significantly slower than the washout of the Non-Penetrating and Non-Targeted CA. Furthermore, the washout of the CatD Targeted CA was significantly slower in the 5XFAD mice compared to the age matched wild-type controls (p <  0.05) at 5 and 12 months of age. Control CAs showed no differences in washout.
  
  
  CONCLUSIONS
  The prolonged retention of the CatD targeted CA in 5XFAD mice suggests this agent may be useful for AD detection.
authors.affiliation: Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada.|Centre for Functional and Metabolic Mapping, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
authors.forename: Jonatan A
authors.initials: JA
authors.lastname: Snir
authors.affiliation: Centre for Functional and Metabolic Mapping, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.|Department of Chemistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Mojmir
authors.initials: M
authors.lastname: Suchy
authors.affiliation: Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada.|Medical Imaging, Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Keith St
authors.initials: KS
authors.lastname: Lawrence
authors.affiliation: Department of Chemistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Robert H E
authors.initials: RH
authors.lastname: Hudson
authors.affiliation: J. Allyn Taylor Centre for Cell Biology, Molecular Brain Research Group, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.|Department of Clinical Neurological Sciences, Schulich School of Medicine, University of Western Ontario, London, Ontario, Canada.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Pasternak
authors.affiliation: Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada.|Centre for Functional and Metabolic Mapping, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Bartha
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002402:Cathepsin D / Q000378:metabolism*; D003287:Contrast Media / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D012372:ROC Curve; D013053:Spectrophotometry; D013997:Time Factors
chemical_list: D016564:Amyloid beta-Protein Precursor; D003287:Contrast Media; C508853:PSEN1 protein, human; D053764:Presenilin-1; D002402:Cathepsin D
keywords: Alzheimer’s disease; Cathepsin D; molecular imaging; optical imaging; transgenic mice