EP2 Knockdown in Macrophages Reduces Inflammation and Restores Cognitive Function in an Alzheimer's Mouse Model
Chronic inflammation is clearly very important in the progression of numerous neurodegenerative conditions, Alzheimer's disease included. Inflammatory signaling, when unrelenting, disrupts cell and tissue function in many tissue types. In recent years, the elimination of lingering senescent cells has been shown in animal studies to reduce inflammation and reverse many of the issues it causes in the aged body. Researchers here take a different approach to suppressing chronic inflammation, sabotaging the ability of macrophage cells to contribute to the inflammatory environment. This has the effect of reversing some of the cognitive decline observed in a mouse model of Alzheimer's disease.
Overexpression of cyclooxygenase-2 (COX-2), a major mediator of inflammation, in the brain produces 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, researchers have 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. They don't phagocytose. They don't clear debris, including misfolded proteins associated with neurodegeneration."
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.