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Blocking Alzheimer’s Disease Process by Blocking Specific Protein

By BiotechDaily International staff writers
Posted on 13 May 2013
Scientists have discovered a potential approach for developing treatments to stop the disease process in Alzheimer’s disease (AD). The strategy is based on unclogging and removing the toxic debris that gathers in patients’ brains, by suppressing activity of a little-known regulator protein called CD33.

“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, PhD, of Massachusetts General Hospital (Boston, MA, USA) and Harvard University (Cambridge, MA, USA), a grantee of the US National Institutes of Health’s (NIH; Bethesda, MD, USA) National Institute of Mental Health (NIMH) and National Institute on Aging (NIA).“Future medications that impede CD33 activity in the brain might help prevent or treat the disorder.”

Dr. Tanzi and colleagues reported their findings April 25, 2013, in the journal Neuron. Variation in the CD33 gene appeared as one of four prime suspects in the largest genome-wide dragnet of Alzheimer's-affected families, reported by Dr. Tanzi and colleagues in 2008. The gene was known to make a protein that controls the immune system, but its function in the brain remained elusive. To find out how it might contribute to AD, the researchers conducted human genetics, biochemistry, and human brain tissue, mouse, and cell-based research.

The scientists found over-expression of CD33 in support cells, called microglia, in postmortem brains from patients who had late-onset AD, the most typical form of the disorder. The more CD33 protein on the cell surface of microglia, the more beta-amyloid proteins and plaques had accumulated in their brains. Moreover, the researchers discovered that brains of people who inherited a version of the CD33 gene that protected them from AD noticeably exhibited reduced amounts of CD33 on the surface of microglia and less beta-amyloid.

Brain levels of beta-amyloid and plaques were also significantly decreased in mice modified to under-express or lack CD33. Microglia cells in these animals were more effective at clearing out the debris, which the researchers tracked to levels of CD33 on the cell surface.

New findings also suggested that CD33 works in league with another AD risk gene in microglia to regulate inflammation in the brain. The study’s findings, as well as those of a recent lab rodent study that replicated numerous characteristics of the human disorder, add support to the prevailing theory that accumulation of beta-amyloid plaques are hallmarks of Alzheimer’s pathology. They come at a time of upheaval in the field, triggered by other recent contradictory findings suggesting that these reputed offenders might instead play a protective role.

Because increased CD33 activity in microglia impaired beta-amyloid clearance in late onset AD, Dr. Tanzi and colleagues are now searching for agents that can cross the blood-brain barrier and block it.

Related Links:

Massachusetts General Hospital
National Institute of Mental Health



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