September 14, 2005

Minnesota Partnership Researchers Publish Alzheimer's Findings

High resolution MR spectroscopy approach could aid drug discovery

MINNEAPOLIS/ROCHESTER, Minn. — A team of researchers from the University of Minnesota and Mayo Clinic say their techniques in high resolution imaging analysis of transgenic mice, mice who have had DNA introduced into one or more of their cells artificially, could speed efforts to find new drug therapies for Alzheimer's disease. The findings, appearing in the Proceedings of the National Academy of Sciences [Marjanska et al. (2005)102, 11906-11910.], mark the first publication of research funded by the Minnesota Partnership for Biotechnology and Medical Genomics.

"The knowledge that one transgenic mouse model seems to undergo the same abnormal neurochemical changes as humans with Alzheimer's disease will benefit researchers conducting preclinical tests of future Alzheimer's drugs," says the University of Minnesota's Michael Garwood, Ph.D., one of three principal investigators on the team.

The researchers, combining the research strengths of their respective institutions, monitored the progression of Alzheimer's disease in three sets of animal models, two transgenic mouse strains bred specifically toward a genomic susceptibility for the disease and a third control group. They then repeatedly scanned the living mice for changes in brain chemicals using proton magnetic resonance spectroscopy (MRS).

Developing techniques to obtain accurate and consistent scans of live subjects over time was one challenge and accomplishment of the study. Another was comparing the subtle changes in the animals' neurochemical profiles to those in the control mice as they aged.

Results showed similarities in age-related chemical changes among all the mice, but results seen in one group of mice (APP-PS1) at 20 months of age agreed most with results from other MRS studies on living humans. The most dramatic change in the mice was a marked increase in the presence of myo-inositol, a chemical thought to be necessary for maintaining osmotic balance in the brain. The mice also showed a decline in levels of N-acetylaspartate (considered a biomarker of neuron number and health) and glutamate(which acts as a neurotransmitter) compared to total levels of creatine, an amino acid responsible for fueling brain function. The researchers say this particular mouse model most closely resembles the experience seen in humans with Alzheimer's disease. However, they say more research is needed to determine if the increase in myo-inositol is due to the genomic makeup of this strain of mice or the proliferation of amyloid plaques developed by the aging mice.

The researchers say that comparisons of the APP-PS1 transgenic mice and normal mice at key ages could prove a highly sensitive live surrogate indicator in Alzheimer's drug trials. They say that studies using MRS technology with this particular strain could be "particularly attractive" to future researchers as their profile parallels that of humans in the same stage of Alzheimer's disease. Because these tests are noninvasive and easily repeatable, MRS in transgenic models of Alzheimer's could substantially accelerate efforts to find new drugs to treat the condition.

The study was lead by three co-investigators: Dr. Garwood and from Mayo Clinic Joseph Poduslo, Ph.D.; and Clifford Jack, M.D. Others on the research team include Malgorzata Marjanska, Ph.D.; Pierre-Gilles Henry, Ph.D.; Robin Bliss; and Kamil Ugurbil, Ph.D., of the University of Minnesota; and Geoffry Curran and Thomas Wengenack, Ph.D., of MayoClinic. Their research was supported in part by the National Institutes of Health, the W.M. Keck Foundation, the MIND Institute, and the Minnesota Partnership for Biotechnology and Medical Genomics.

The Minnesota Partnership is a unique statewide research initiative involving the State of Minnesota and its premier medical research institutions — the University of Minnesota and Mayo Clinic.

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