The definitive diagnosis of Alzheimer's disease currently requires post-mortem examination. Our preliminary evidence shows that the Abeta peptide can be labeled with gadolinium (Gd) and be used following systemic injection for the detection of amyloid lesions in vivo in AD transgenic mouse models by magnetic resonance imaging (MRI) (using APPSW and APPsw/PS1 Tg mice). Gadolinium is currently widely used in clinical imaging as a contrast agent. A majority of parenchymal amyloid deposits can be detected using this method, providing potential approaches for both the early detection of amyloid lesions (when they may be most amenable to therapeutic intervention) and also monitoring the response to amyloid clearing therapy in vivo. Both these goals have become critically important since the recent demonstrations that immunization with human Abeta1-42 reduces Abeta deposition and prevents cognitive decline in Tg models of AD. However, this immunization method may be problematic in humans since we and others have shown that Abeta1-42 crosses the blood-brain barrier (BBB), where it is neurotoxic and can seed amyloid formation. In addition, the Freund's adjuvant used in these immunization experiments is too toxic for human use. Our preliminary evidence suggests that vaccination with non-fibrillar, non-toxic Abeta homologous peptides produces dramatic amyloid reductions in Tg AD models. In this application we plan to further develop the amyloid imaging methodology by altering the ligand to limit any potential toxicity and to increase BBB permeability, as well as using single chain and other anti- Abeta Gd labeled antibodies for imaging. We will also further test the efficacy of our non-toxic Abeta homologous peptides for vaccination in conjunction with alum based adjuvants (which are approved for human use), as well as testing passive immunization with anti- Abeta antibodies, which our preliminary results show can disaggregate pre-formed Abeta peptide fibrils. Importantly we will be able to subject immunized Tg mice to in vivo MRI in order to follow amyloid clearance. Vaccinated and imaged mice will be subject to behavioral testing to determine if cognitive deficits can be prevented by this approach. Our preliminary results indicate that APP/PS1 Tg aged mice have significant cognitive impairments versus controls. These studies will provide essential information before such approach can be safely used in humans.
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