E.Excessive inflammation is a problem of aging and contributes to problems such as atherosclerosis, cancer, and cognitive decline. However, the mechanisms of age-related inflammation are not exactly known. In a study published today (January 20) in nature, Researchers show that older immune cells have a metabolic defect that, when corrected in a mouse model of Alzheimer’s disease, can reduce inflammation and restore cognitive function.
After a decade of advances in understanding the metabolism and nutrient consumption in immune cells and how they affect their function, this study is a “fine example” that we now know enough to intervene, push buttons, and influence results, Eyal says Amiel, who studies immune cell metabolism at the University of Vermont and was not involved in the new work. “Having a particular metabolic signature associated with a pathology is one thing. To be able to manipulate it is another matter. It is an incredible sequence of events to be able to manipulate and reverse the pathology. “
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 like ibuprofen and naproxen had an occasional reduced risk of pain for Alzheimer’s. During her postdoc in Paul Worley’s lab at the Johns Hopkins School of Medicine, she and her colleagues demonstrated that overexpression of Cyclooxygenase-2 (COX-2) – a major mediator of inflammation – in the brain led to Alzheimer’s-like symptoms in mice: age-related inflammation and cognitive loss.
COX-2 activation is the first step in making a lipid called prostaglandin E.2 (PGE2), which binds to one of its receptors, EP2, on immune cells and can promote inflammation. To clog the pathway, Andreasson’s group has shown that deleting the EP2 receptor in mouse macrophages and brain-specific microglia – the cells normally responsible for recognizing and destroying immune invaders and cell debris – reduces inflammation and increases neuronal survival in response both bacteria increased toxin and a neurotoxin.
In the current study, the researchers wanted to understand how PGE is eliminated2 Signal transmission in macrophages could have these effects. They started by comparing macrophages from human blood donors who were either younger than 35 or older than 65 years. The cells from older donors produced much more PGE2 and had a higher frequency of the EP2 receptor than macrophages from younger donors. When researchers exposed human macrophages to PGE2the cells have changed their metabolism. Instead of using glucose to produce energy, the cells converted it into glycogen and stored it. They locked them up where the mitochondria couldn’t access them for ATP production.
“The result is that the cells are basically low in energy. They’re just tired and not working well, ”explains Andreasson. “You don’t phagocytize. They don’t clear rubble. “These debris contain misfolded proteins that are associated with neurodegeneration, the authors write in the paper.
When the scientists treated human macrophages from donors, mean age about 48 years, with one of two EP2 receptor inhibitors, glycogen storage decreased, energy production increased, and cells were moved to express anti-inflammatory markers. As in human cells, aged mice have higher levels of PGE2 in 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 one of the two drugs to suppress EP2 function, the cells had improved metabolism. The age-related inflammation of the mice was also reversed, and with it the age-related cognitive decline. Treatment of animals with an EP2 antagonist, which could not get into the brain and thus only targeted the receptor in peripheral macrophages, also led to cognitive improvement in older mice.
“The most interesting thing they were able to show is that the macrophages are the cause of the age-related cognitive decline and are particularly sufficient to reprogram the macrophages outside the brain,” says Jonas Neher, neuroimmunologist at the German Center for Neurodegenerative Diseases and the University of Tübingen in Germany, who wrote an accompanying comment. The next steps are to “find out which signal is coming from the periphery and changing the microglia in the brain. If you can identify that particular signal, then you have another grip on how to reprogram microglia. “
“The hypothetical clinical promise of these results is obviously excellent in that, as you can imagine, no brain surgery or any type of high-risk intervention would be required,” says Amiel. “Rather, you can systematically manipulate cells and see these results.”
Studying how these systemic effects work is just one of the questions Andreasson’s group is currently pursuing. They are also interested in how and why metabolism decreases with aging, as well as other mechanisms that could prevent it. In terms of transferring the work to the clinic, one of the only ways to target the EP2 receptor is by putting COX-2 inhibitors like Vioxx, a drug that has been withdrawn from the market after some experience of the market, way upstream to bring about strokes or heart attacks. There are still no drugs that specifically block the EP2 receptor, says Andreasson The scientist. “There have been attempts by pharmaceutical companies, but from my understanding it has been very, very difficult.”
PS Minhas et al., “Restoring the Metabolism of Myeloid Cells Reverses the Cognitive Decline of Aging” nature, doi: 10.1038 / s41586-020-03160-0, 2021.