Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Medical Biophysics

Supervisor

Drs. Robert Bartha

2nd Supervisor

Stephen Pasternak

Joint Supervisor

Abstract

Background: Currently there is no widely accepted test to diagnose AD. The involvement of the lysosomal system in Alzheimer’s disease (AD) progression provides an opportunity to develop associated biomarkers. The lysosomal enzyme Cathepsin D (CatD) has been shown to be over-expressed in the AD brain before clinical onset. We have developed a dual modality contrast agent (CA) to detect CatD activity which consists of an HIV-1 Tat Cell Penetrating Peptide (CPP) conjugated to a CatD cleavage sequence and two imaging moieties consisting of a fluorescently- tagged probe and a DOTA cage for chelating Gallium-68. The purpose of this work was to validate CatD as an AD biomarker across multiple AD disease models and to test our novel CA in-vivo by means of optical near infra-red (NIR) fluorescence imaging and positron emission tomography (PET). Methods: Three transgenic (Tg) mouse AD model strains were tested for CatD expression by Western blot and immunohistochemistry analysis. The chosen mouse line (5XFAD) and controls were imaged at 5 and 12 months of age using an eXplore Optix scanner (GE Healthcare, Milwaukee, WI, USA). Next, mice at 2, 6 and 9 months of age were tested using an Inveon microPET system (Siemens Medical Solutions, Knoxville TN, USA) using a 68Ga-labeled CatD targeted CA. Results: All 3 AD mice demonstrated an elevation of CatD expression in parallel with AD pathology. The 5XFAD had the highest levels of CatD, making it the best mouse model to study CatD upregulation. The rate of the NIR CatD Targeted CA washout was significantly slower in the 5XFAD mice (p

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