Cancer-related protein has Alzheimer's linkA protein that allows human cancer to resist multiple anticancer drugs also appears to play a key role in Alzheimer’s disease, according to research conducted by Kenneth D. Tew, Ph.D., D.Sc., the new chair of the Department of Cell and Molecular Pharmacology and Experimental Therapeutics.The research was conducted by Tew and his colleagues at the Fox Chase Cancer Center in Philadelphia. The report will appear in the July issue of the Federation of American Societies for Experimental Biology Journal. Tew’s research concentrated on understanding and circumventing mechanisms of cellular resistance to anticancer drugs and understanding cellular pathways that affect drug response and resistance. The new report concerns the human ABCA2 transporter, one of a large family of ATP-binding proteins that transport a variety of molecules across biological membranes. ATP (adenosine triphosphate) is present in all living cells and serves as a major energy source for cellular reactions. Related transporter proteins with varying functions (there are more than 50 coded for by the human genome) are widely expressed in human tissues, according to Tew. “The overexpression of the ABCA2 protein has been implicated in acquired resistance of tumors to the drug estramustine, which is used to treat prostate cancer patients,” explained Tew, senior author of the paper. “This transporter is also expressed at high levels in brain tissue and may be linked with the transport of molecules relevant to the etiology of Alzheimer’s disease, including those involved in the formation of amyloid plaques. The association of the transporter with Alzheimer’s first emerged from a comparative gene expression pattern analysis that we did.” To analyze small changes in gene expression with little material, his laboratory developed Amplified Differential Gene Expression (ADGE) technology and ADGE microarray (“gene chip” technology for rapid analysis of gene expression) to examine cell lines made to express high levels ABCA2 protein. The microarray analysis revealed alterations in gene clusters related either to transport function or to oxidative stress response. This observation tied in with metabolism of free radicals and of beta-amyloid, a primary component of Alzheimer’s disease plaques, consisting of dense deposits of protein and cellular material. According to Tew, ABCA2 can play a role in cholesterol transport and also in myelination—an “insulation” for nerve cells in mammals and other vertebrates. Because these neurons are longer than other cells, they are more vulnerable to damage. Myelin protects them by sheathing their axons—threadlike extensions of the nerve cells—in alternating layers of protein and fat. A new model of human brain aging (Neurobiology of Aging, January 2003) postulates that mid-life breakdown of myelin could be a possible key to the later development of Alzheimer’s disease. “Imaging studies and examination of brain tissue have shown that the deterioration of myelin triggers degeneration of complex neural connections,” Tew said. “This may be due to genetic factors as well as the brain’s process of increasing cholesterol and iron levels in middle age. “In samples of brain sections from Alzheimer’s patients, the ABCA2 protein shows unusual patterns of expression,” Tew added. “That also suggests that this transporter has a role in Alzheimer’s.” Grants from the National Institutes of Health and a Commonwealth of
Pennsylvania appropriation helped support the work.
Friday, May 28, 2004
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