One of the major changes that occur during aging is the dysregulation of the immune response which is responsible for a persistent pro-inflammatory state and may cause a decline in cognitive functions, metabolic syndrome, atherosclerosis, and cancer. In the aged brain, microglia lose their ability to remove misfolded proteins that are associated with neural degenerations. Previously, the exact mechanism that correlates inflammation with aging was not known. In a recent study, scientists studying the mouse model of Alzheimer’s disease, an age-associated neurodegenerative disorder, have been able to correlate the defect in the metabolism of the older immune cells and inflammation. They also claimed that a decrease in inflammation can reestablish cognitive functions.
Katrin Andreasson, a Professor at Stanford University’s School of Medicine, observed that using nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen could lessen the risks of Alzheimer’s disease. In earlier research, she and her colleague at Johns Hopkins School of Medicine found that overexpression of cyclooxygenase-2 (COX-2), a major target of NSAIDs, promotes inflammation in the brain cells that leads to Alzheimer’s disease-like symptoms in mice.
Scientists have reported that activation of the COX-2 gene is responsible for the production of prostaglandin E2 (PGE2). When this lipid molecule binds to the receptor (EP2) on immune cells, inflammation occurs. Andreasson and her research team observed that deletion of EP2 receptor in mouse macrophages and brain-specific microglia had markedly reduced inflammation. Subsequently, an increase in the surviving capacity of neural cells, in response to neurotoxins and bacterial toxins, took place.
To understand the role of inflammation in aging, scientists have compared the macrophages from human blood donors under the age of 35 with those older than 65. They found the concentration of PGE2 and EP2 receptors was significantly higher in older donors. Further, when the macrophages were exposed to PGE2, instead of making energy from glucose, the cells converted glucose to glycogen, and thereby, the mitochondria failed to produce ATP. This makes the cells fatigued and also promotes neurodegenerations.
Furthering their research, scientists treated human blood macrophages (donors with an average age of about 48) with one of two EP2 receptor inhibitors. They found that glycogen storage decreased and an increase in energy production took place. Additionally, there was an increase in the expression of anti-inflammatory markers.
Similar to humans, macrophages of aged mice have a higher level of PGE2 in the blood and EP2 receptor levels compared to younger mice. Scientists found improvements in metabolism when they removed EP2 receptors from the mouse model of Alzheimer’s disease. Similar results were also obtained when animals were treated with drugs to suppress EP2 function. Further, a reversal of age-related inflammation and decline in cognitive function was also observed.
Jonas Neher, a neuroimmunologist at the University of Tübingen in Germany, stated that the most important point of this study is the understanding of the role of macrophages in age-related cognitive decline.
In future work, researchers will focus on understanding the mechanisms behind the factors that change the microglia in the brain. This could lead to the reprogramming of microglia and reverse the age-related decline in cognitive functions.