Blocking a gene's activity could clear beta-amyloid plaques in Alzheimer's
Researchers from Massachusetts General Hospital and Harvard University have discovered a possible new mechanism to halt the disease process in Alzheimer's. Blocking the activity of a little-known protein could clear beta-amyloid plaques that form in the brains of Alzheimer's patients--a hallmark of the disease.
In 2008, after setting out on a huge genome-wide search of families with Alzheimer's sufferers, researchers found that variation in the CD33 gene turned up as one of four prime suspects of the disease. Scientists knew the gene was responsible for making a protein that regulates the immune system, but didn't grasp its relationship to the brain.
"Too much CD33 appears to promote late-onset Alzheimer's by preventing support cells from clearing out toxic plaques, key risk factors for the disease," explained Rudolph Tanzi, of Massachusetts General Hospital and Harvard University. "Future medications that impede CD33 activity in the brain might help prevent or treat the disorder."
Analyzing genetics data, researchers detected over-expression of CD33 in support cells, called microglia, in postmortem brains from patients who had late-onset Alzheimer's disease. They observed that the more CD33 protein on the cell surface of microglia, the more beta-amyloid proteins and plaques had accumulated in their brains. In people who didn't develop Alzheimer's but who inherited a version of the CD33 gene, their brains showed reduced amounts of CD33 on the surface of microglia and less beta-amyloid. The research appeals in the journal Neuron.
In animal studies, researchers engineered mice to under-express or lack the CD33 genes altogether. In these animals, brain levels of beta-amyloid and plaques were considerably low, and the animals' microglia cells were better at clearing plaques in the brain.
Inflammation in the brain might also occur due to fluctuations in CD33 alongside another Alzheimer's risk gene in microglia, according to the study.
Tanzi and his colleagues, whose research was funded by the National Institutes of Health, are now searching for agents that can cross the blood-brain barrier to block the activity of CD33.
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