The Worldwide Wave
Research on inflammation hits ALS shores.

Five years ago, Thomas Moeller wouldn’t have shown his face at an investigators’ meeting—the Packard Center’s monthly lectures for its scientists. It’s not that the University of Washington researcher isn’t accomplished. No doubt of that. But nobody thought then that an expert on inflammation in the central nervous system would say anything remotely useful about ALS. To suggest a role for the immune system was, scientifically, a ticket to nowhere on a fast train.

But Moeller persisted, and this spring his guest lecture on

Moeller—now vindicated.

microglia, the central nervous system’s live-in immune cells, brought engaged questions from Center researchers. It’s part of Packard policy to invite experts whose work brings a fresh look at ALS biology or therapy. “I’m riding a worldwide wave of interest in inflammation that extends to stroke, epilepsy, multiple sclerosis and neurological disease in general,” Moeller explains.

Tiny and difficult to study, microglia make up about 10 percent of brain and spinal cord tissue. And like most immune system cells, they’re active during inflammation. They branch out, structurally, and move where there’s injury. But in a misguided defense posture, microglia also release toxic

A "riled" microglial cell.

molecules that injure neurons. It’s this result, Moeller feels, that accelerates ALS. As he pithily puts it, “When microglia are tickled, they get nasty.” Understanding what activates the cells—a focus of his research—could bring ways to slow the disease.

Two Center scientists have helped shape Moeller’s work. Two years ago, Jean-Pierre Julien showed that the antibiotic minocycline not only damps down microglia but it also extends the life of SOD1 mouse models of Lou Gehrig’s disease. More recently, Don Cleveland’s studies have suggested how microglia might fit into the disease’s downhill path, at least for inherited ALS.

For some time, Cleveland has sought ALS’s starting point in the nervous system. In animal models where every cell carries the disease-causing mutant SOD1 gene, he categorically removes that gene from different types of nervous system cells to see how that affects the disease. The fact that Cleveland’s rats lived three months longer than usual when their microglia were free of mutant SOD1 says that something about having flawed SOD1 in those cells hastens an animal’s death.

Microglia in ALS model mice become well-activated long before symptoms appear, and they do indeed produce deadly chemicals, Moeller has found. They also underproduce natural protective agents. “So it’s a double whammy,” he explains.

Something activates microglia—like mutant protein in the inherited disease or something injured cells release, perhaps, in the more common sporadic ALS. “We know for certain that activated microglia accelerate the disease,” says Moeller. “That tells us you could potentially slow ALS down, defuse it.”

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