Alzheimer’s plaques due to purging flaw

Disease-related gene controls clearance of plaque protein

The high-risk version of a gene associated with Alzheimer’s disease hinders the brain’s ability to clear out a troublesome protein, a new study finds.

PLAQUE ATTACK How much plaque builds up in the brains of mice genetically engineered to get Alzheimer’s disease depends upon which version of the cholesterol-handling APOE protein the animals have. The APOE e4 version is a risk factor for Alzheimer’s disease in people and inhibits clearance of the plaque-forming protein from mice’s brains. Image courtesy of Joseph M. Castellano, David M. Holtzman

Researchers have known that people who carry the e4 version of the gene APOE are at higher risk for Alzheimer’s disease and more likely to have cell-killing plaques in their brains than people who have the e3 or e2 versions. But it hasn’t been clear whether people with the e4 version made more of the plaque protein — called amyloid-beta — or if the stuff just stuck around in their brains longer.  

Now researchers led by David Holtzman of the Washington University School of Medicine in St. Louis have directly measured levels of amyloid-beta in the brain fluid of mice. The measurements, reported in the June 29 Science Translational Medicine, show that mice with the e4 version of APOE make amyloid-beta at the same rate and in the same amount as mice with different versions of the gene, but don’t clear the protein out of their brains as efficiently.

The study will probably draw more attention to the role amyloid-beta clearance plays in Alzheimer’s disease, says Caleb Finch, a neurobiologist and codirector of the Alzheimer Disease Research Center at the University of Southern California. “I think this is a valuable contribution,” he says.

It is not yet clear how different forms of the protein made by APOE govern clearance of amyloid-beta from the brain, says Joseph Castellano, a neuroscientist working in Holtzman’s lab. “We don’t understand that at all,” he says.

The researchers would like to know if the APOE protein and amyloid-beta interact directly or if there are middlemen involved. Figuring out the connection could lead to preventive therapies that would stop the buildup of amyloid-beta.

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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