Reducing plaque formation in AD models

Michael McDonald, PhD
University of Tennessee, Health Science Center (Memphis, TN)
Year Awarded:
2007
Grant Duration:
April 1, 2007 to March 31, 2009
Disease:
Alzheimer's Disease
Award Amount:
$150,000
Grant Reference ID:
A2007174
Award Type:
Pilot
Award Region:
US Southeastern

Targeting GD3S to reduce plaque and improve memory

Summary

We propose to use siRNA to suppress GD3S expression in a mouse model of Alzheimer's disease. Consistent with our previous results, we expect that this novel genetic therapy will significantly reduce plaque formation and completely block the memory deficits normally exhibited by these mice.

Details


Alzheimer's disease is characterized by the accumulation of plaques in the brain, widespread neurodegeneration, and cognitive decline. We have shown that by eliminating an enzyme called GD3S we are able to reduce plaque formation, block cell death, and prevent memory deficits in a mouse model of Alzheimer's disease. This suggests that blocking GD3S may useful in treating Alzheimer's disease. However, in these mice the mutation that blocked GD3S was made before birth, and the enzyme plays an important role in many processes that are important for normal brain development. Thus it's important to test the therapy in adult mice, after they've gone through normal brain development. This is analogous to what a genetic therapy will be like for Alzheimer's patients, i.e., the treatment begins in adulthood. A new technique, called siRNA, allows us to simply and efficiently suppress the expression of the GD3S gene in live mice. We propose to use siRNA to suppress GD3S expression in a mouse model of Alzheimer's disease. Consistent with our previous results, we expect that this novel genetic therapy will significantly reduce plaque formation and completely block the memory deficits normally exhibited by these mice.

Publications

Bernardo, A., Harrison, F.E., McCord, M., Zhao, J., Bruchey, A., Davies, S.S., Jackson Roberts, L. 2nd, Mathews, P.M., Matsuoka, Y., Ariga, T., Yu, R.K., Thompson, R., McDonald, M.P. (2008) Elimination of GD3 synthase improves memory and reduces amyloid-beta plaque load in transgenic mice. Neurobiol Aging. Feb 5;  

Reiserer, R.S., Harrison, F.E., Syverud, D.C., McDonald, M.P. (2007) Impaired spatial learning in the APPSwe + PSEN1DeltaE9 bigenic mouse model of Alzheimer's disease. Genes Brain Behav. Feb;6(1):54-65.  

Bazalakova, M.H., Wright, J., Schneble, E.J., McDonald, M.P., Heilman, C.J., Levey, A.I., Blakely, R.D. (2007) Deficits in acetylcholine homeostasis, receptors and behaviors in choline transporter heterozygous mice. Genes Brain Behav. 2007 Jul;6(5):411-424.  

Bernardo, A., McCord, M., Troen, A.M., Allison, J.D., McDonald, M.P. (2007) Impaired spatial memory in APP-overexpressing mice on a homocysteinemia-inducing diet. Neurobiol Aging. 2007 Aug;28(8):1195-1205.  

Dhanushkodi, A., Bindu, B., Raju, T.R., Kutty, B.M. (2007) Exposure to enriched environment improves spatial learning performances and enhances cell density but not choline acetyltransferase activity in the hippocampus of ventral subicular-lesioned rats. Behav Neurosci. 2007 Jun;121(3):491-500.  

Dhanushkodi, A. and Shetty, A.K. (2007) Is exposure to enriched environment beneficial for functional post-lesional recovery in temporal lobe epilepsy? Neurosci Biobehav Rev. 2007 Nov 28.  

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