A substance that increases brain inflammation also unexpectedly helps clear away the protein deposits characteristic of the disorder, according to a new study. Though unlikely to translate directly into a human treatment, the findings may open up new approaches against Alzheimer’s, as well as help to clarify its effects on the brain.
Over many years, the protein beta-amyloid forms sticky “plaques” in the brains of people with Alzheimer’s, ultimately killing the surrounding neurons and causing memory loss and other cognitive problems. Inflammation, caused by excessive action by the brain’s immune cells (called microglia), is another hallmark of the disease. Researchers generally assumed that inflammation equates with injury and toxicity to neurons, but whether microglia make plaque buildup better or worse was unclear.
To investigate, Pritam Das and colleagues at the Mayo Clinic in Jacksonville, Fla., tested whether a higher degree of brain inflammation would increase the amount of plaques. Working with mice genetically altered to develop an Alzheimer’s-like condition, the researchers used a modified virus to over-produce the protein interleukin-6 (IL-6). IL-6 is one of the so-called cytokines, which immune cells and some neurons use to exchange messages. Some cytokines stimulate immune system activity, while others work to call it off. IL-6 is known to be highly inflammatory, and it is prevalent in the brains of patients with Alzheimer’s disease.
Turning up IL-6 sent the microglia into overdrive, as expected. But the upshot, much to the researchers’ surprise, was a decrease in the amount of amyloid plaques. Adult, newborn and two-day-old mice showed a significant reduction in plaques, compared with untreated control animals of the same age. Newborn mice showed reductions of up to 79 percent, and in a few animals, amyloid plaques were almost undetectable in some brain areas. The study appeared online Oct. 14 in The FASEB Journal, published by the Federation of American Societies for Experimental Biology.
“It’s possible the microglia ‘think’ the plaques are a foreign object, like viruses or bacteria, and they try to remove them from the brain but can’t quite manage it,” Das says. “Turning up IL-6 might give the microglia the boost they need.”
Making things better
Terrence Town at Cedars Sinai Medical Center and the University of California, Los Angeles, was surprised to see that IL-6 seems to clear plaques from the brain. “You’d expect that increasing inflammation would make matters worse,” he says. “But the study is thorough and the results are conclusive.” And because the researchers used two different strains of disease-prone mice, at three different age points, the research is particularly convincing, he says.
Of course the actions of microglia in the brain are complex, and questions remain. Although Das and colleagues found no signs of neurotoxicity resulting from IL-6 treatment, Town says a future study that examines surrounding neurons in greater detail could rule out any possibility of “bystander damage.” He also observes that the current study does not extend to checking the microglia for amyloid fragments, which would have proved that the glia gobble up the plaques the way they would an invading organism.
Das agrees that no research team, so far, has shown that microglia devour amyloid plaques in the brains of living animals, though some studies with cultured microglia have suggested as much. He also cautions that his study has other limitations. For example, the reduction in plaques is based on comparison to control animals, not to the amount of plaque the mice started out with; the investigators are now developing the more-complex study design needed to test for that. They also plan on evaluating memory and behavior in the treated mice in the future.
Das is encouraged, however, to see no evidence that IL-6 administration makes plaque buildup worse. And though minute damage to surrounding neurons is a possibility, IL-6 so far lacks the toxic side effects observed with other inflammatory cytokines his team has studied.
A complicated picture
Unfortunately, turning up IL-6 is not a treatment option for humans, Das says, because the cytokine has widespread effects throughout the body. “A better therapeutic approach would be to work out the mechanism for its actions that’s specific to microglia, and then find a way to activate that pathway,” he says.
Town notes that because of the complex relationship among microglia, plaques, and many types of cytokines, we should not jump to conclusions; other research in the area has yielded confusing and unexpected results. In a paper published in the June 1, 2008, Nature Medicine, Town’s lab studied a cytokine called transforming growth factor beta (TGF beta), which normally works to quell the immune response. The team studied mice that carry Alzheimer’s disease genes and have a genetically “interrupted” immune response to TGF beta. But instead of seeing “runaway inflammation,” as Town puts it, the researchers found protein plaques in the animals’ brains, and the mice performed better in mazes designed to test spatial memory.
And in a study appearing in the November 2009 Nature Neuroscience, Mathias Jucker and colleagues at the University of Tübingen, Germany, experimentally removed all microglia from the brains of “Alzheimer mice,” with no effect at all on amyloid plaque formation. This study suggests that microglia do not go after plaques under normal circumstances, but leaves open the question of whether experimental intervention might turn them into plaque removers.
“There’s a lot of work still to be done to clarify what happens in a brain with Alzheimer’s disease—which immune or inflammatory pathways might be beneficial and which are deleterious,” Town says. “It’s truly an exciting time, and great that the research community is looking carefully, on the molecular level, at which approaches are the best to take forward in terms of treatment.”