Amyloid Plaque Degradation by Matrix Metalloproteinase9

JinMoo Lee, MD, PhD
Washington University (St. Louis, MO)
Year Awarded:
2006
Grant Duration:
April 1, 2006 to March 31, 2008
Disease:
Alzheimer's Disease
Award Amount:
$300,000
Grant Reference ID:
A2006033
Award Type:
Standard
Award Region:
US Midwestern

Amyloid Plaque Degradation by Matrix Metalloproteinase9

Summary

Since Dr. Alois Alzheimer initially described the disease that bears his names, amyloid plaques have been a hallmark of the disease. Dr. Lee’s team is investigating the role of a specific enzyme believed to be involved in controlling rate of plaque growth. The inquiry into nature’s way of eliminating toxic amyloid will offer scientists new opportunities to leverage this process in future therapeutics.

Details

One of the major abnormalities found in the brains of patients with Alzheimer's disease (AD) are clumps of abnormally aggregated protein, called amyloid plaques. These proteins (amyloid-beta peptide) have a remarkable propensity to self-aggregate into long chains of protein known as amyloid fibrils, which are thought to be very resistant to breakdown and clearance. Thus, it is believed that the plaques accumulate in the brains of patients with Alzheimer's disease, contributing to brain degeneration and leading to dementia. Dr. Lee has recently found an enzyme, matrix metalloproteinase-9 (MMP-9), capable of degrading amyloid fibrils in test tube experiments. He has also found that MMP-9 degrades amyloid plaques in brain slices from a mouse model of AD. Furthermore, he finds that this enzyme is found in cell surrounding amyloid plaques in this mouse model, suggesting that it may play a role in regulating the growth of plaques. In this grant application, Dr. Lee proposes to study the role of MMP-9 in degrading amyloid plaques in a mouse model of Alzheimer's disease. He plans to use genetically altered AD mice that lack MMP-9 to examine the formation of amyloid plaques, asking the question: “Is plaque formation accelerated in AD mice that lack MMP-9?” Furthermore, this research will determine if MMP-9 limits the size of amyloid plaques once they are formed. Dr. Lee hopes to gain further insight into mechanisms that regulate the growth and degradation of amyloid plaques in Alzheimer's disease

Publications

Yan P., Hu X., Song H., Yin K., Bateman R.J., Cirrito J.R., Xiao Q., Hsu F.F., Turk J.W., Xu J., Hsu C.Y., Holtzman D.M., Lee J.-M. Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ. J Biol Chem, 281(34):24566-24574, 2006.  

Yin K.J., Cirrito J., Yan P., Hu X., Xiao Q., Pan X., Bateman R, Song H, Hsu F.F., Turk J, Xu J, Hsu C.Y., Mills J., Holtzman DM, Lee J.M. Matrix metalloproteinases expressed by astrocytes mediate extracellular Abeta catabolism. J Neurosci, 26(43):10939-48, 2006.  

Vetrivel, K.S., Zhang, X., Meckler X., Cheng H., Lee S., Gong P., Lopes K.O., Chen Y., Iwata N., Yin K.-J., Lee J.-M., Parent A.T., Saido T.C., Li Y.-M., Sisodia S.S., Thinakaran G. Evidence that CD147 modulation of ABeta levels is mediated by extracellular degradation of secreted ABeta, J Biol Chem, 283(28):19489-98, 2008.  

Daginakatte G.C, Gadzinski A., Emnett R.J., Stark J.L., Gonzales E.R., Yan P., Lee J.-M., Cross A.H., Gutmann D.H., Expression profiling identifies a molecular signature of reactive astrocytes stimulated by cyclic AMP or proinflammatory cytokines, Exp Neurol, 210:261-7, 2008.  

Lee J.-M., Blennow K., Andreasen N., Laterza O., Modur V., Olander J., Gao F., Ohlendorf M., Ladenson J.H., The Brain Injury Biomarker, VLP-1, is increased in the CSF of Alzheimer's Disease patients, Clin Chem, 54(10):1617-23, 2008.  

Zhang R., Hu X., Khant H., Ludtke S.J., Chiu W., Schmid M.F., Frieden C., Lee J.-M., Inter-protofilament interactions between Alzheimer's ABeta1-42 peptides in amyloid fibrils revealed by cryo-EM, Proc Natl Acad Sci, 24:106(12):4653-8, 2009.  
 

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