Prolonged In Vivo Retention of a Cathepsin D Targeted Optical Contrast Agent in a Mouse Model of Alzheimer's Disease

J Alzheimers Dis. 2015;48(1):73-87. doi: 10.3233/JAD-150123.

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.

Keywords: Alzheimer’s disease; Cathepsin D; molecular imaging; optical imaging; transgenic mice.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology*
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Brain / metabolism*
  • Cathepsin D / metabolism*
  • Contrast Media / metabolism*
  • Disease Models, Animal
  • Humans
  • Magnetic Resonance Imaging
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation / genetics
  • Presenilin-1 / genetics
  • ROC Curve
  • Spectrophotometry
  • Time Factors

Substances

  • Amyloid beta-Protein Precursor
  • Contrast Media
  • PSEN1 protein, human
  • Presenilin-1
  • Cathepsin D