A new Northwestern Medicine study found that the immune system in the blood of Alzheimer’s patients is epigenetically altered. This means that the patients’ behavior or environment has caused changes that affect the way their genes work.
Many of these altered immune genes are the same ones that increase a person’s risk for Alzheimer’s. Northwestern scientists theorize that the cause may be a previous viral infection, environmental pollutants, or other lifestyle factors and behaviors.
“It is possible that these findings implicate the regional immune response in Alzheimer’s disease risk,” said lead researcher David Gate, assistant professor of neurology at Northwestern University Feinberg School of Medicine. “We have yet to unravel whether these changes reflect brain pathology or accelerate the disease.”
The study was published February 9 in Neuron.
Previous research has shown that many of the mutated genes that put a person at higher risk for Alzheimer’s are in the immune system. But the scientists primarily studied the central immune system in the brain, because Alzheimer’s is a brain disease. They have largely ignored the immune system in the blood, also known as the peripheral immune system.
Gate decided to study the blood. He and his colleagues discovered that every type of immune cell in Alzheimer’s patients has epigenetic changes, indicated by open chromatin. Chromatin is the packaging of DNA inside cells. When chromatin is open — or exposed — the cell’s genome is vulnerable to alteration.
Next, Gate looked at which genes are most turned on in these immune cells. He discovered that one receptor — CXCR3 — on T cells was more exposed. Gate believes that CXCR3 acts like an antenna on T cells that allows the cells to enter the brain. T cells normally do not enter the brain because they can cause inflammation.
“The brain sends out a signal that it’s damaged, and T cells turn to that signal through their antenna, CXCR3,” Gate said.
“The cells may be very toxic to the brain, but we also don’t know if these cells may be trying to repair damage to the brain,” Gate said.
Gate also discovered epigenetic changes in inflammatory proteins in white blood cells called monocytes.
“Taken together, these findings show that immune function in Alzheimer’s patients is significantly altered,” Gate said. “It could be that environmental factors, such as pollutants or infections that a person has in their life, cause these epigenetic changes.”
The findings revealed several genes that may be therapeutic targets for manipulating the peripheral immune system. The next steps in the research are preclinical studies using in vitro culture systems and animal models to test these targets.
Other Northwestern authors include Abhirami Ramakrishnan, Natalie Piehl, Brooke Simonton, Milan Parikh, Ziyang Zhang, Victoria Teregulova, and Lynn van Olst.
The title of the article is “Epigenetic dysregulation in peripheral immunity in Alzheimer’s disease”.
The research is supported by National Institute of Neurological Disorders and Stroke grant NS112458 and National Institute on Aging AG078713, both of the National Institutes of Health, the Bright Focus Foundation, the Alzheimer’s Association, and the Alzheimer’s Cure Fund.