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Mapping out how an Alzheimers gene works could lead to new treatments.

So far, nearly two dozen genes scattered across four chromosomes have been linked to an increased risk of Alzheimers disease. But identifying such genetic risk factors doesnt mean that researchers fully understand how they contribute to cognitive decline and dementia. And that understanding is often crucial to turning genetic information into effective treatments.

Now a group of scientists report in the journal Neuron that they have pieced together the back story of one gene, known as CD33, that could lead to exciting new ways of removing the amyloid plaques that build up in the brains of Alzheimers patients and cause so many problems with memory and cognitive functions.

(MORE: New Research on Understanding Alzheimers)

Dr. Rudolph Tanzi, director of the genetics and aging research unit at Massachusetts General Hospital and professor of neurology at Harvard Medical School, and his team first identified CD33 in 2008, and at the time, he says, We had no idea what this thing did. And in the [scientific research] literature, little was known about it. So we started from scratch.

Beginning with studies of the where the gene was expressed, he found that a subset of brain cells known as microglia seemed to show high levels of CD33, which makes receptors that pop up on the surface of the cells to bind to neuronal debris, including the residue of inflammatory reactions, and dead and dying nerve cells. CD33 functions as a molecular housekeeper, patrolling the nervous system for any material that doesnt belong and could impair normal brain function. That includes the deposits of amyloid protein that build up in the brains of Alzheimers patients, eventually forming sticky plaques that compromise normal nerve function before destroying them.

(MORE: First Genes Linked to Higher Risk of Alzheimers Disease Among African-Americans)

But when Tanzis team looked at the brains of patients who had died of Alzheimers, they found that CD33 also had a darker side. In patients with a higher burden of amyloid plaques, CD33 also appeared in excess. And so did tons of dead neurons. At some point, as the amyloid is making the cells sick, and forming tangles as lots of neurons are dying, the microglia put on their battle gear and turn radical, killing whatever they think is attacking the brain, says Tanzi. The result is friendly fire, and they start to kill so many neurons that the microglia are now detrimental; they are no longer clearing but theyre rounding up nerve cells and shooting out free radicals and causing a lot of damage.

Instead of engulfing and removing the amyloid, microglia armed with CD33 were targeting healthy nerves instead. To confirm that, Tanzis team conducted a series of tests with cells in culture and in animals, and found that when microglia were stripped of CD33, they went back to performing their housekeeping duties as expected, sniffing out amyloid and pulling the protein out of circulation. Mice genetically engineered to develop Alzheimers plaques but without CD33 showed lower levels of amyloid plaques in their brains than animals with the gene, suggesting that the CD33 was clearing the protein away.

Excerpt from:
How an Alzheimer's Gene Could Lead to New Treatments

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