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Immune protein may be culprit behind dementia and hypertension link

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Researchers at Weill Cornell Medicine researching the relationship between hypertension and dementia have uncovered the immune protein called cytokine IL-17 as a potential culprit for inducing dementia and suggest new approaches to prevent damage to brain cells.

Their findings are published in Nature Neuroscience in an article titled, “Meningeal interleukin-17-producing T cells mediate cognitive impairment in a mouse model of salt-sensitive hypertension.”

“Hypertension (HTN), a disease afflicting over one billion individuals worldwide, is a leading cause of cognitive impairment, the mechanisms of which remain poorly understood,” the researchers wrote. “In the present study, in a mouse model of HTN, we find that the neurovascular and cognitive dysfunction depends on interleukin (IL)-17, a cytokine elevated in individuals with HTN. However, neither circulating IL-17 nor brain angiotensin signaling can account for the dysfunction. Rather, IL-17 produced by T cells in the dura mater is the mediator released in the cerebrospinal fluid and activating IL-17 receptors on border-associated macrophages (BAMs).”

“An increase in blood pressure is not what hits the brain to cause dementia,” explained senior author Costantino Iadecola, PhD, the Anne Parrish Titzell professor of neurology and director and chair of the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine. “That may be important for the heart, putting an excessive load that makes the heart pump harder. But as far as cognitive impairment, our data suggest that one of the major causes is this IL-17 immune response.”

“There has been some debate as to whether managing blood pressure with hypertensive drugs is enough to prevent cognitive decline,” said first author Monica Santisteban, PhD, who is currently an assistant professor of medicine at Vanderbilt University Medical Center.

Hypertension in humans is linked to T cells of the immune system releasing more IL-17, causing increased levels circulating throughout the body. This led them to focus on IL-17 and its potential connection to cognitive health. Normally, IL-17 is part of the immune response to pathogens but can contribute to inflammatory diseases.

The researchers replicated cognitive issues in a preclinical model with increased IL-17 levels. IL-17, produced by T cells in the gut and the circulatory system, is involved in decreasing blood flow to the brain by acting on endothelial cells that line the inside of blood vessels. Lack of necessary blood flow can damage brain cells. So, the researchers eliminated IL-17 receptors on endothelial cells to block that interaction and to see if this prevented cognitive impairment. However, Iadecola and his team found even after blocking the effects of IL-17 on the brain, cognitive issues remained.

They then examined the protective membrane around the brain called the meninges, since past studies pointed to immune cells, and a potential source of IL-17, in this area. Isolating the dura, the outermost layer of the meninges, the team located T cells that produced Il-17 independent of the gut. They also discovered that the Il-17 was able to infiltrate the brain since the arachnoid, the middle layer in the meninges, was damaged. IL-17 interacted with receptors on brain-associated macrophages which induced oxidative stress that caused tissue injury and suppressed necessary blood flow to the brain.

These findings uncover a previously unknown critical role that T cells in the meninges and IL-17 play in the cognitive impairment associated with salt-sensitive hypertension.

Iadecola and Santisteban believe this finding creates opportunities to study new combination therapies. Avenues could include adding IL-17 inhibitors to treat cognitive impairment with conventional treatments for reducing blood pressure.

“More research will be looking at what other cell types in the dura are contributing to the relationship between hypertension and dementia,” said Santisteban. “But the biggest takeaway here is that managing blood pressure may not be enough to manage cognitive decline.”

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