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A Probable Treatment for Alzheimer’s Disease: Somewhere Between Confusion and Clarity The Transthyretin Protein Edgewood SMART Team: R. Cray, W. Grosenheider, S. Huntoon, T. Johnson, C. Lee, E. Madsen, C. McLaughlin, M. Popp, J. Power, K. Ralph, S. Rothrock, N. Sekhon, E. Sharata Teacher: Mr. Dan Toomey Mentor: Dr. Jeffrey A. Johnson, University of Wisconsin – Madison, School of Pharmacy lzheimer’s disease currently affects an estimated 4.5 million Americans. The progressive degenerative neurological Adisorder is commonly associated with memory loss and intellectual impairments concerning speech, skilled movements, and recognition. Discovered in the early 1900s by German psychiatrist Alois Alzheimer, the specific cause of the disease is not known, though the presence of Alzheimer’s disease has been connected to abnormal folding of the amyloid beta (A-beta) protein in the brain. Today, Alzheimer’s disease is the eighth leading cause of death in the United States, with over 63,000 fatalities accounted for. Alzheimer’s disease is also the third most costly disease in the country, costing the U.S. over $100 billion each year. T Alois Alzheimer, the German psychiatrist who discovered Alzheimer’s disease. he A-beta protein and transthyretin are two proteins of interest to scientists trying to understand how Alzheimer’s disease develops. The disease results from the accumulation of a specific fragment of the amyloid precursor protein. When this small piece of protein is cut from the amyloid precursor protein, the smaller piece is referred to as the A-beta protein. The A-beta protein forms plaques by aggregating together (shown in Figure 1), as well as causing neurons in the brain to die, resulting in Alzheimer’s disease. Transthyretin, however, is the “good protein” and prevents the A-beta protein from killing those neurons. Though researchers do not specifically know how the transthyretin does this, it is hypothesized that the transthyretin binds with the A-beta so that it cannot interact with the neurons. FIGURE 1 tudies have shown that mice genetically engineered to have higher levels of the A-beta protein also have more transthyretin, therefore preventing Alzheimer’s-like pathology from occurring in the mice. Shown below in Figure 2 are examples from the mouse experiment. Boxes C and E are enlarged from Box A to show portions of the hippocampus (a part of the brain found in the temporal lobe concerned with memory) of the control mouse. Boxes D and F show the enlarged portions of the hippocampus of the mouse that over expressed the mutant amyloid precursor protein and had high levels of Abeta. The brown areas shown in Figure 2 in boxes B, D, and F represent the presence of the transthyretin protein, showing FIGURE 2 how much the mouse’s brain has increased transthyretin levels to protect CONTROL APP MICE itself from the induced A-beta increases and neuronal cell death. This increase in transthyretin, unfortunately, only happens in mice, and has not been seen in humans living with Alzheimer’s disease. Because mice have dramatically increased transthyretin levels, which block the A-beta toxicity, researchers are trying to find ways of increasing that protein in humans. S The comparison of a healthy brain cell and a brain cell with Alzheimer’s disease. Inc., is a biopharmaceutical company Mithridion, founded by Dr. Jeffrey Johnson and his colleagues, Comparison of transthyretin levels in the brain between the control mouse and the mouse with genetically increased A-beta levels. with the mission of discovering and developing new drugs to treat Alzheimer’s and other neurodegenerative diseases (Figure 3). Having patented findings from the mouse experiment, Mithridion, Inc., aims to develop a drug that will mimic the protein in a mouse’s brain, sAPPalpha, not found in humans, that causes increased transthyretin levels in the mouse brain. This drug could protect humans from the toxicity of A-beta and stop the progression of Alzheimer’s disease. The company hopes to have a drug available to the public within the next few years. Supported by the National Institutes of Health (NIH) – National Center for Research Resources Science Education Partnership Award (NCRR-SEPA) FIGURE 3 M D K Neuroprotective sAPPα α A E V T E 602 amino acids F E E R S H I D S Neuroprotective fragments E DRUG LEAD K H Y Neuroprotective tetrapeptide (4 amino acids) from sAPPalpha Q H G V Transthyretin protects neurons from A-beta toxicity From Bench to Bedside Mithridion, Inc. is breaking new ground in Alzheimer’s research and drug development. Disclosure: Dr. Jeff Johnson has an ownership interest in Mithridion, Inc., which has an exclusive license of the technology reported in this slide.