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Mapping out how an Alzheimer’s 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 Alzheimer’s disease. But identifying such genetic risk factors doesn’t 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 Alzheimer’s patients and cause so many problems with memory and cognitive functions.

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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 doesn’t belong and could impair normal brain function. That includes the deposits of amyloid protein that build up in the brains of Alzheimer’s patients, eventually forming sticky plaques that compromise normal nerve function before destroying them.

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But when Tanzi’s team looked at the brains of patients who had died of Alzheimer’s, 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 they’re 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, Tanzi’s 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 Alzheimer’s 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.

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That clearance could be the key to alleviating some of the worst symptoms of the disease, experts say, since most people make amyloid protein but for some reason it starts to accumulate as we age. “What we discovered is that CD33 is a key switch so when the switch is off, and it is deactivated, there is more clearance of [amyloid,]” says Tanzi. “If we can now find drugs that inactivate CD33 it should allow more clearance of [amyloid] by the microglial cells.”

His group is already screening compounds to find those that might block CD33 from turning rogue, but the search will have to balance compounds that do a good job of keeping CD33 honest without compromising its ability to seek and destroy real invaders, as it was designed to do. “It’s something we have to keep an eye on for sure,” says Tanzi of the possibility that a CD33 blocker to treat Alzheimer’s could compromise immune functions and make patients more vulnerable to infections or other health issues.

But the discovery could be an important step toward finally developing an effective Alzheimer’s drug treatment, since clearing amyloid plaques could be critical in addressing the deposits of amyloid that mushroom throughout the brain as the disease progresses. “We just need to take advantage of the housekeeping functions of CD33 and entice them to stay helpful and not go crazy,” says Tanzi.

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