Knocking out the receptor for a lipid that causes inflammation rejuvenates macrophage metabolism and restores cognitive function in an Alzheimer’s disease model.
Excess inflammation is a problem in aging, contributing to issues such as atherosclerosis, cancer, and cognitive decline. But the mechanisms behind age-related inflammation are not well understood. In a study published today (January 20) in Nature, researchers show that older immune cells have a defect in metabolism that when corrected in a mouse model of Alzheimer’s disease can decrease inflammation and restore cognitive function.
After a decade of progress in understanding metabolism and nutrient usage in immune cells and how that affects their function, this study is a “beautiful example” of now knowing enough to intervene, push buttons, and influence outcomes, says Eyal Amiel, who studies immune cell metabolism at the University of Vermont and was not involved in the new work. “To have a specific metabolic signature associated with a pathology is one thing. To be able to manipulate it is another thing. To be able to manipulate it and reverse the pathology is an incredible sequence of events.”
As a postdoc in the late 1990s, Katrin Andreasson, now a neurologist and researcher at Stanford University School of Medicine, was intrigued by epidemiological studies showing that people who took nonsteroidal anti-inflammatory drugs—such as ibuprofen and naproxen—occasionally for aches and pains had a decreased risk of Alzheimer’s disease. During her postdoc in Paul Worley’s lab at Johns Hopkins School of Medicine, she and her colleagues showed that overexpression of cyclooxygenase-2 (COX-2)—a major mediator of inflammation—in the brain led to Alzheimer’s disease-like symptoms in mice: age-dependent inflammation and cognitive loss.
COX-2 activation is the first step in the production of a lipid called prostaglandin E2 (PGE2), which can bind to one of its receptors, EP2, on immune cells and promote inflammation. To plug up the pathway, Andreasson’s group has shown that deleting the EP2 receptor in mouse macrophages and brain-specific microglia—the cells normally responsible for detecting and destroying immune invaders and cellular debris—reduces inflammation and increases neuronal survival in response to both a bacterial toxin and a neurotoxin.
In the current study, the researchers wanted to understand how eliminating PGE2 signaling in macrophages could have these effects. They started by comparing macrophages from human blood donors either younger than 35 or older than 65. The cells from older donors made much more PGE2 and had higher abundance of the EP2 receptor than did macrophages from younger donors. When the researchers exposed human macrophages to PGE2, the cells altered their metabolism. Rather than using [ … ]