Fight Against Alzheimers, Multiple Sclerosis Gets New Target

St. Louis, MO - Washington University - infoZine - Working with mice, two research teams at Washington University School of Medicine in St. Louis independently linked the protein to the ability to clear debris from the brain. Such waste builds up both as a byproduct of daily mental activities and as a result of misdirected immune system attacks on brain cells. If too much debris is present in the brain for too long, it can contribute to neurological disease.

In one study, appearing online Feb. 26 in Cell, scientists showed that Alzheimers brain plaques build up more slowly in mice that have a defective version of the TREM2 protein. In another, published Jan. 29 in Acta Neuropathologica, researchers showed that mice lacking the same protein had trouble cleaning up debris in the brain produced by damage to a protective coating on nerve cells. The problem is thought to occur in MS and other neurological disorders.

Scientists are looking for ways to activate the protein to slow or prevent damage caused by neurological disorders.

Previous studies have linked rare forms of the TREM2 gene to early-onset dementia and increased risk of Alzheimers disease, Parkinsons disease and amyotrophic lateral sclerosis (ALS).

Scientists knew the protein was found on brain cells called microglia, which help maintain and repair the central nervous system. The new studies are among the first to provide clear evidence that the protein plays an integral role in at least some of these processes.

In Alzheimers disease, amyloid beta, a byproduct of brain metabolism that is normally cleared from the brain, builds up to form plaques. Researchers in the laboratories of Marco Colonna, MD, the Robert Rock Belliveau MD Professor of Pathology, and John Cirrito, PhD, associate professor of neurology, bred mice lacking the gene with mice genetically engineered to have an Alzheimers-like condition.

First author Yaming Wang, PhD, a postdoctoral research scholar, monitored the buildup of amyloid plaques in the mice offspring as they aged and found that the absence of the gene significantly accelerated the accumulation of the plaques.

We found that microglia cluster around amyloid plaques when TREM2 is present, presumably because the cells are getting ready to absorb the plaques and break them down, said Colonna. When TREM2 is absent, this clustering does not occur.

In MS, misdirected immune cell attacks damage myelin, a protective coating on nerve cells, leaving myelin fragments in brain tissue. Failure to promptly remove this debris can worsen damage caused by the condition and inhibit repair mechanisms.

For the MS study, Piccio and colleagues at the John L. Trotter MS Center at Washington University School of Medicine and Barnes-Jewish Hospital gave a compound called cuprizone to mice that lacked the TREM2 gene. Cuprizone causes loss of myelin in a manner somewhat similar to that seen in people with MS.

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Fight Against Alzheimers, Multiple Sclerosis Gets New Target