Inflammation has long been known as a factor in the progression of Alzheimer’s disease, but the specifics of its role are not completely understood. Researchers at Massachusetts General Hospital took a step toward identifying how and when neuroinflammation (inflammation of tissue in the brain and nervous system) causes the death of neurons in people with Alzheimer’s.
In a study published recently in Nature Neuroscience, researchers led by Rudolph Tanzi, PhD, director of the Genetics and Aging Research Unit in the Mass General Institute for Neurodegenerative Disease, built upon what was dubbed the “Alzheimer’s in a dish” system. Several years ago, MGH scientists were able to reproduce the disease process of Alzheimer’s in a laboratory setting. The culture in the original study replicated the beta amyloid protein plaques and tau protein tangles commonly associated with Alzheimer’s, but did not include neuroinflammation in the study. That research was published in 2014 in the journal Nature.
In the new study, Dr. Tanzi and his colleagues incorporated glial cells, which normally patrol the brain looking for signs of infection or inflammation. These signs include chemicals produced by beta-amyloid, the toxic protein that appears to destroy synapses—the communication connections between brain cells. The glial cells, or microglia, release cytokines, which are substances that activate more microglia to help eliminate the cause of the inflammation.
Unfortunately, in the brain of someone with Alzheimer’s, glial cells can become overactive, triggering unhealthy levels of cytokines—essentially causing more neuroinflammation instead of reducing inflammation in the brain.
Dr. Tanzi notes that studying the formation and growth of plaques and tangles reveals only two parts of the story behind brain cell death in a person with Alzheimer’s. “Studies have shown that we can have many plaques and tangles in our brains with no symptoms, but when neuroinflammation kicks in, exponentially more neurons die and cognitive impairment leading to dementia is induced,” he explains. “A complete model of Alzheimer’s pathology needs to incorporate that ‘third leg of the stool’.”
Inflammation may be the “third leg of the stool,” when it comes to Alzheimer’s disease, but it’s also something of a double-edged sword. This is true of inflammation anywhere in the body.
Inflammation is part of the body’s immune response. If you cut your finger, the inflammatory response kicks in, sending white blood cells to the site of the cut to help fight off infection. But that’s acute inflammation, and when the threat is contained, your immune system retreats to its routine, calmer state.
But in the case of chronic inflammation, healthy cells suffer and die over time. In the brain, microglia can be effective at attacking beta amyloid plaque and removing damaged cells. But their enthusiasm can be too much of a good thing, as healthy neurons perish and AD progresses in an environment of elevated inflammation.
The Path of Inflammation
In the MGH study, researchers wanted to see how microglia behaved in a lab-based AD setting. The scientists, led by Hansang Cho, PhD, co-senior author of the study and now with the University of North Carolina at Charlotte, used a microfluidic device composed of two circular chambers, one inside the other. The device allowed the researchers to track the migration of microglia from the outer chamber through channels into the inner chamber containing neurons that had been cultured to contain beta amyloid and tau.
Human microglia were added to the outer chamber and soon began to change structurally. They migrated to the inner chamber and immediately attacked neurons. While this was going on, levels of pro-inflammatory cytokines changed significantly. Six days later, the inner chamber had lost 20 percent of its neurons.
The researchers also focused on two microglial cell receptors that respond to cytokines and boost inflammatory activity. “We found that blocking two receptors in microglial cells – interferon receptor gamma and toll-like receptor 4 – could prevent neuroinflammation, which opens up new opportunities for drug discovery,” says Dr. Tanzi, who is the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School. “This system should help us better understand the timeline by which these pathological events lead to dementia and enable us to screen for drugs that stop plaque deposition, tangle formation and the resultant neuroinflammation.”