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Memory loss and other Alzheimer’s-like features reversed in mice

The mass die-off of nerve cells in the brains of people with Alzheimer’s disease may largely occur because an entirely different class of brain cells, called microglia, begin to fall down on the job, according to a new study by researchers at the Stanford University School of Medicine.

The researchers found that, in mice, blocking the action of a single molecule on the surface of microglia restored the cells’ ability to get the job done — and reversed memory loss and myriad other Alzheimer’s-like features in the animals.

The study, published online in the Journal of Clinical Investigation, illustrates the importance of microglia and could lead to new ways of warding off the onset of Alzheimer’s disease, which is predicted to afflict 15 million people by mid-century unless some form of cure or prevention is found. The study also may help explain an intriguing association between aspirin and reduced rates of Alzheimer’s.

Microglia, which constitute about 10-15 percent of all the cells in the brain, actually resemble immune cells considerably more than they do nerve cells.

“Microglia are the brain’s beat cops,” said Katrin Andreasson, MD, professor of neurology and neurological sciences and the study’s senior author. “Our experiments show that keeping them on the right track counters memory loss and preserves healthy brain physiology.”

Implicated: a single molecule

A microglial cell serves as a front-line sentry, monitoring its surroundings for suspicious activities and materials by probing its local environment. If it spots trouble, it releases substances that recruit other microglia to the scene, said Andreasson. Microglia are tough cops, protecting the brain against invading bacteria and viruses by gobbling them up. They are adept at calming things down, too, clamping down on inflammation if it gets out of hand. They also work as garbage collectors, chewing up dead cells and molecular debris strewn among living cells — including clusters of a protein called A-beta, notorious for aggregating into gummy deposits called Alzheimer’s plaques, the disease’s hallmark anatomical feature.

A-beta, produced throughout the body, is as natural as it is ubiquitous. But when it clumps into soluble clusters consisting of a few molecules, it’s highly toxic to nerve cells. These clusters are believed to play a substantial role in causing Alzheimer’s.

“The microglia are supposed to be, from the get-go, constantly clearing A-beta, as well as keeping a lid on inflammation,” Andreasson said. “If they lose their ability to function, things get out of control. A-beta builds up in the brain, inducing toxic inflammation.”