by Abby Olena
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 glucose to make energy, the cells converted it to glycogen and stored it, locking it up where the mitochondria couldn’t access it for ATP production.
“The result of that is that the cells are basically energy-depleted. They’re just fatigued, and they don’t work well,” explains Andreasson. “They don’t phagocytose. They don’t clear debris.” This debris includes misfolded proteins associated with neurodegeneration, the authors write in the paper.
When the scientists treated human macrophages from donors with an average age of about 48 with one of two EP2 receptor inhibitors, glycogen storage decreased, energy production increased, and cells shifted to express anti-inflammatory markers. As in human cells, aged mice also have higher levels of PGE2 in the blood and brain and EP2 receptor levels in macrophages, compared to younger mice. When the researchers knocked down the receptor in macrophages throughout the body in a mouse model of Alzheimer’s disease or treated animals with either of two drugs to suppress EP2 function, cells had improved metabolism. The mice’s age-associated inflammation also reversed and, with it, age-associated cognitive decline. Treating animals with an EP2 antagonist that couldn’t get in the brain and thus only targeted the receptor in peripheral macrophages also led to cognitive improvement in older mice.
“The most interesting thing that they were able to show is that the macrophages are causal in driving age-associated cognitive decline, and, in particular, that it’s sufficient to reprogram the macrophages outside of the brain,” says Jonas Neher, a neuroimmunologist at the German Center for Neurodegenerative Diseases and the University of Tübingen in Germany who authored an accompanying commentary. The next steps are “to figure out what the signal is that comes from the periphery and changes the microglia in the brain. If you can identify this particular signal, then you have another handle on how to reprogram microglia.”
“The hypothetical clinical promise of these findings is obviously outstanding because as you can imagine, it wouldn’t require brain surgery or any kind of gross-level, high-risk intervention,” says Amiel. “Rather, you can manipulate cells systemically and see these outcomes.”
Investigating how those systemic effects work is just one of the questions that Andreasson’s group is currently pursuing. They’re also interested in how and why metabolism declines during aging, as well as other mechanisms that might prevent it. In terms of translating the work to the clinic, one of the only ways to target the EP2 receptor is to go far upstream with COX-2 inhibitors, such as Vioxx, a drug that was withdrawn from the market after some people who took it experienced strokes or heart attacks. There aren’t any drugs that specifically block the EP2 receptor yet, Andreasson tells The Scientist. “There have been attempts made by pharmaceutical companies, but my understanding is it’s been very, very difficult to do.”
P.S. Minhas et al., “Restoring metabolism of myeloid cells reverses cognitive decline in ageing,” Nature, doi:10.1038/s41586-020-03160-0, 2021.