Affiliations: [a] Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada | [b] Centre for Functional and Metabolic Mapping, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada | [c] Department of Chemistry, University of Western Ontario, London, Ontario, Canada | [d] Medical Imaging, Lawson Health Research Institute, London, Ontario, Canada | [e] J. Allyn Taylor Centre for Cell Biology, Molecular Brain Research Group, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada | [f] Department of Clinical Neurological Sciences, Schulich School of Medicine, University of Western Ontario, London, Ontario, Canada
Correspondence:
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Correspondence to: Robert Bartha, PhD, Centre for Functional and Metabolic Mapping, Robarts Research Institute, 100 Perth Drive, London, Ontario, N6A 5K8, Canada. Tel.: +1 519 663 5777/ Ext. 24039; Fax: +1 519 931 5224; [email protected]
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.
