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

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

Author information

1
Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada.
2
Centre for Functional and Metabolic Mapping, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
3
Department of Chemistry, University of Western Ontario, London, Ontario, Canada.
4
Medical Imaging, Lawson Health Research Institute, London, Ontario, Canada.
5
J. Allyn Taylor Centre for Cell Biology, Molecular Brain Research Group, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
6
Department of Clinical Neurological Sciences, Schulich School of Medicine, University of Western Ontario, London, Ontario, Canada.

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

PMID:
26401930
DOI:
10.3233/JAD-150123
[Indexed for MEDLINE]

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