This Protein May Protect Against Alzheimer's, Scientists Say

In the search for a treatment for Alzheimer's disease, researchers have zeroed in on a protein with protective effects.

A new study reveals how cholesterol and inflammation in different types of human brain cells interact with a protein called ABCA7, which regulates how molecules pass through cell membranes.

Reduced levels of ABCA7 in human brain cells may be a trigger for Alzheimer's, and the team thinks their new information could be used to develop treatments.

"We show that cholesterol depletion reduces ABCA7 levels in human microglia and astrocyte but not neuronal cells," writes the team from the Alzheimer's Center at Temple University in Philadelphia.

Past research by two of the authors of the current study found that brain ABCA7 levels decrease with age, and people with lower levels are more likely to develop Alzheimer's disease earlier in life.

That built on discoveries about gene variants of ABCA7 in Alzheimer's disease patients from genome-wide association studies with thousands of participants.

"But genome studies only point to a protein and do not tell us anything about how it functions or how it affects a disease," says neuroscientist Joel Wiener.

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"Our goal is to reveal ABCA7's functions and to use what we learn about its role in pathology to turn it into an effective therapy against Alzheimer's disease."

Cholesterol and chronic inflammation have been implicated in Alzheimer's disease, but there's much we don't know about these two factors.

Inflammation helps fight infections and heal damaged tissue, but it's a complex process. Chronic inflammation can damage healthy tissues and organs and lead to serious health conditions.

In our brains, immune cells called microglia mostly regulate inflammation, though supporting cells called astrocytes also play a part, along with neurons.

Weiner and colleagues performed a series of experiments on human microglia, astrocytes, and neuron cell lines cultured in the lab. After removing some cholesterol, they treated the brain cells with rosuvastatin, a medication that inhibits cholesterol production.

When around half to three-quarters of the normal cholesterol was removed from the cells, the levels of ABCA7 decreased by about 40 percent in microglia cell lines and by about 20 percent in an astrocyte cell line.

Next, the researchers administered three different cytokines – small, inflammation-triggering proteins secreted by our immune cells – to the brain cell lines.

In microglia, two of the cytokines suppressed ABCA7 expression, and the third cytokine showed no impact at all on ABCA7. None of the three cytokines induced any changes in ABCA7 levels in astrocytes or neurons.

"Overall, cholesterol depletion and inflammation may reduce ABCA7 levels in the brain and cause the onset of Alzheimer's disease," says Wiener.

It's possible the loss of ABCA7 in Alzheimer's may be due to an abrupt change in cholesterol metabolism, or an inflammatory response.

The team say their results support the idea that ABCA7 keeps lipid balance in the brain by clearing cholesterol that could damage nerve cells. But inflammation appears to temporarily lower ABCA7 levels, which can become a problem when inflammation doesn't resolve.

This might explain why people with multiple sclerosis, which involves high levels of inflammatory cytokines, are more likely to develop Alzheimer's.

"The greatest challenge now is to figure out how to measure ABCA7 levels in the brain of living humans," neuroscientist Nicholas Lyssenko explains.

"If we achieve this, we could verify whether inflammation suppresses ABCA7 in the human body."

The progressive and devastating effects of Alzheimer's disease on brain structure and function manifest in a wide range of cognitive and behavioral changes over time.

The only treatments for Alzheimer's disease focus on reducing symptoms and slowing the disease's progression, but there is currently no cure.

"Effective testing for ABCA7 levels in the brain will also identify individuals who are at greater risk for Alzheimer's disease," says Lyssenko, "and spur the development of new ABCA7-based therapies."

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