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Workings of an Alzheimer’s Gene

NIH-funded scientists have discovered a potential strategy for developing treatments to stem the disease process in Alzheimer’s disease. It’s based on unclogging removal of toxic debris that accumulates in patients’ brains, by blocking activity of a little-known regulator protein called CD33. Too much CD33 activity may promote late-onset Alzheimer’s by preventing support cells from clearing out toxic plaques. Future medications that impede CD33 activity might help prevent or treat the disorder. Dr. Thomas Lehner, director of NIMH’s Office of Genomics Research Coordination, explains the significance of the new findings.

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DR. THOMAS LEHNER: The hope of the large-scale genetic studies is always, first, to find a signal. That is, to find a gene that's associated with a particular disorder - Alzheimer's in this case. And then, the next very difficult step is to then take this finding and move it forward into developing new drugs. Rudy Tanzi and his colleagues did exactly that. They took the finding and through a complex set of experiments in human brains, in cells, in mice - they actually could show, with strong confidence, that this gene and its product, is associated as a risk for Alzheimer's disease.

The gene involved, according to the study, is called CD33. We know it's involved in immune function somehow. But we don't know what it does in the brain. It is expressed - the protein that's coded by CD is produced in cells in the brain that are called microglia. Microglia are support cells that protect the brain from infection - that have an immune function in the brain.

CD33 is also involved in clearance of a protein beta-amyloid has long been associated with Alzheimer's. And CD33 helps to get rid of the over-production of that protein. The gene comes in two flavors. And it has been shown that one particular flavor is protective for Alzheimer's. And it also reduces the level of beta-amyloid that's present in the brain.

If the expression of CD33 is reduced in those particular microglial cells - these protective, support cells that have immune function. If the expression is reduced, the cells themselves can take up higher quantities of beta-amyloid, and eliminate beta amyloid - thus protecting the brain from Alzheimer's.

Until today, very few genetic signals have been found that increase the risk for Alzheimer's disease. Now, through large-scale genomic studies of recent years, we have a few more. Not too many, maybe three or four. This is one of those.

One of the reasons this finding is so exciting is that it opens a potential pathway to develop treatments. You could imagine that if there was a drug developed that crosses the blood-brain barrier - which is an additional difficulty - that oppresses the expression of that particular gene, that may be protective for Alzheimer's. But his is, you know, far. This is nothing that is imminent. This is a long process of drug development.