? This project will test the hypothesis that modifications of amyloid-beta protein (A beta) or derivatives of A beta can be used for the molecular imaging of amyloid plaques in Alzheimer's disease (AD). This is based on the observation that not only does AI3 provide the seed for the formation of plaques, but it also binds to pre-existing plaques with high affinity and facilitates their growth. Various derivatives of A beta will be examined and compared to A beta 1-40, including A beta 1-30, which excludes the cell surface binding domain (A beta 31-34); A beta 1-25, which excludes the neurotoxic domain (A beta 25-35); and A beta 1-15, which excludes the aggregation domain (A beta 16-20). It is particularly important to develop a derivative of A beta that is non-toxic. We have solved an important problem regarding the delivery of A beta 1-40 across the blood-brain barrier (BBB) after systemic administration by using polyamine-modified A beta, which results in an increase in the permeability coefficient x surface area product (PS) of the protein at the BBB. Polyamine modification increases the binding of A beta to amyloid plaques in AD brain tissue sections. Furthermore, we have demonstrated that polyamine-modified A beta 1-40 labels plaques in vivo following intravenous injection in a transgenic mouse model of AD. Our preliminary results document the success of this molecular probe, now coupled with an MRI contrast agent, gadolinium, in addition to the polyamine, putrescine, to label AD amyloid plaques throughout the cortex, hippocampus, and other brain regions of AD transgenic mice following intravenous injection. We are able to image individual plaques using high-field-strength 7-Tesla magnetic resonance imaging (MRI) with high resolution and observe alterations in T1-weighted (T1W) and T2-weighted (T2W) relaxation that are probe specific.
The Specific Aims reflect the further development of this contrast agent for characterizing and quantifying the deposition of amyloid plaques in AD transgenic mice by MRI. Although this research may raise numerous questions concerning the feasibility of MR imaging of AD plaques in humans, we believe that the specific aims listed will facilitate answers to these questions in a logical manner by minimizing neurotoxicity, by optimizing the molecular probe for targeting and binding to AD plaques, and by optimizing imaging parameters both ex vivo and in vivo in the AD transgenic mouse. All of these steps are clearly necessary before application to the AD patient. The ability of this MR contrast agent to image plaques in vivo in the AD transgenic mouse may enable early diagnosis of the AD patient and also provide a direct measure of the efficacy of anti-amyloid therapies currently being developed. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG022034-02
Application #
6752087
Study Section
Diagnostic Radiology Study Section (RNM)
Program Officer
Molchan, Susan
Project Start
2003-06-01
Project End
2008-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
2
Fiscal Year
2004
Total Cost
$565,665
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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Yao, Jeffrey K; Wengenack, Thomas M; Curran, Geoffry L et al. (2009) Reduced membrane lipids in the cortex of Alzheimer's disease transgenic mice. Neurochem Res 34:102-8
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Wengenack, Thomas M; Jack Jr, Clifford R; Garwood, Michael et al. (2008) MR microimaging of amyloid plaques in Alzheimer's disease transgenic mice. Eur J Nucl Med Mol Imaging 35 Suppl 1:S82-8
Jack Jr, Clifford R; Marjanska, Malgorzata; Wengenack, Thomas M et al. (2007) Magnetic resonance imaging of Alzheimer's pathology in the brains of living transgenic mice: a new tool in Alzheimer's disease research. Neuroscientist 13:38-48
Poduslo, Joseph F; Ramakrishnan, Muthu; Holasek, Silvina S et al. (2007) In vivo targeting of antibody fragments to the nervous system for Alzheimer's disease immunotherapy and molecular imaging of amyloid plaques. J Neurochem 102:420-33
Hartman, Tyler K; Wengenack, Thomas M; Poduslo, Joseph F et al. (2007) Mutant mice with small amounts of BubR1 display accelerated age-related gliosis. Neurobiol Aging 28:921-7
Kandimalla, Karunya K; Wengenack, Thomas M; Curran, Geoffry L et al. (2007) Pharmacokinetics and amyloid plaque targeting ability of a novel peptide-based magnetic resonance contrast agent in wild-type and Alzheimer's disease transgenic mice. J Pharmacol Exp Ther 322:541-9

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