A new study published in the online edition of the journal Acta Neuropathologica has dealt a blow to the idea that anti-inflammatory drugs might protect people struggling with dementia from Alzheimer's disease. Inflammation of microglia—an abundant cell type that plays an important supporting role in the brain—does not appear to be associated with dementia in Alzheimer's disease, say researchers with the McKnight Brain Institute of the University of Florida, in collaboration with scientists at the University of Frankfurt, Germany. The researchers say their findings support recent clinical trial results that indicate anti-inflammatory drugs are not effective at fighting dementia in patients with Alzheimer's disease, which affects about 5.3 million Americans.

 

“For almost 20 years now, it's been claimed that brain inflammation contributes to the development of Alzheimer's disease dementia, and based on that claim, numerous clinical trials with anti-inflammatory drugs have been conducted,” says Wolfgang Streit, a professor of neuroscience at the College of Medicine. “They have been unsuccessful.”

 

Mark Smith, a professor of pathology at Case Western Reserve University and editor-in-chief of the Journal of Alzheimer's Disease, says the paper potentially represents “a paradigm shift in the way we look at Alzheimer's disease.” Smith, who did not participate in the study, says it challenges the popular idea of neuro-inflammation and instead makes a good case that the miroglia cells are subject to aging.

 

The researchers showed that the brain's immune system, made up of microglia, is not activated in the brains of Alzheimer's patients, as would be the case if there were inflammation. Instead, they say, microglia are degenerating. They argue that a loss of microglial cells contributes to the loss of neurons, and leads to the development of dementia. Microglial cells are a subset of a very large population of brain cells known as glial cells. Neurons are the workhorse cells of the brain, enabling thought and movement, but glia provide neurons physical and nutritional support.

 

Glial cells, which outnumber neurons 10-to-1, are at the heart of a popular explanation for Alzheimer's disease that suggests protein fragments called beta amyloid clump together in the spaces between brain cells, causing memory loss and dementia. Inflammation theories suggest that microglia become activated and mount an immune response to these protein clumps, and instead of being helpful, a toxic release of chemicals occurs, worsening the disease effects.

 

However, high-resolution observations did not find evidence that beta amyloid activates, or inflames, human microglia cells. Nor did researchers find evidence that inflammation is to blame for brain cell death. Using a commercially available antibody, the researchers the first time created a marker for microglial cells in human brain specimens that had been in chemical storage. The specimens were from 19 people with varying degrees of Alzheimer's, ranging from severe to none at all. Two of the samples were from Down syndrome patients, who are known to develop Alzheimer's pathology in middle age.

 

When researchers examined these cells alongside neurons under a high-resolution microscope, they found that—unless an infection had occurred elsewhere in the body—microglial cells from Alzheimer's patients were not distinctly larger or unusually shaped, which would have been the case had they been inflamed.

 

“What I expected to see is activated microglia right next to dying neurons,” Streit says. “That is what I did not find. What I propose is glia are dying, and the neurons lose support. We now need to find out what caused glia to degenerate. Rather than trying to find ways to inhibit microglia with anti-inflammatory drugs, we need to find ways to keep them alive and strong. It's a whole new field.”