news release
Monday, December 4, 2023
An NIH-funded study in mice suggests a potential new target for treating hypertension.
Research supported by the National Institutes of Health suggests that a response of immune system cells in the protective membrane that surrounds the brain may contribute to the cognitive decline that can occur in people with chronic hypertension. . This discovery is natural neuroscience, may shed light on new ways to counter the effects of high blood pressure on cognition. This study was funded by the National Institute of Neurological Disorders and Stroke (NINDS), part of the NIH.
“Understanding the role of immune signaling in cognitive decline is critical,” said Dr. Roderick Corriveau, NINDS program director. “These findings provide insight into how signaling from the immune system contributes to the symptoms of cognitive decline that ultimately lead to the diagnosis of dementia.”
High blood pressure affects more than 1 billion people worldwide and can cause cognitive decline not only when a stroke occurs, but even when a person with high blood pressure does not have a stroke. However, efforts to control cognitive decline in people who have not had a stroke with blood pressure-lowering treatments have shown mixed results. The results of this mouse study suggest that under conditions that mimic common hypertension, immune cells around and within the brain become abnormally activated, and that this activation leads to impaired brain function.
Researchers led by Dr. Costantino Iadecola, president and director of the Feil Family Brain and Mind Institute in New York City, used a mouse model of hypertension to investigate the effects of interleukin-17 (IL-17). It was discovered that the level had increased abnormally. A chemical normally released in the body, cerebrospinal fluid, and brain to activate the immune system. Previously, Dr. Iadekola's team showed that a high-salt diet increases IL-17 in the intestine, followed by cognitive impairment. These new findings further deepen the story by showing that IL-17 is acting within the brain itself. It is also worth noting that these experiments used a different mouse model called the DOCA salt model, which more closely mimics common hypertension in humans.
“This is the most realistic model of hypertension that we have at this time,” Dr. Iadecola said. “DOCA mice simulate low-renin hypertension, a type of hypertension that is common in people, especially black Americans.”
Further research has shown that when IL-17 enters the brain, it activates immune cells known as macrophages, which are responsible for activating inflammation and fighting infections. A series of experiments showed that both mice with brain macrophage deletion of IL-17 receptors and mice with brain macrophage depletion showed no effect of hypertension on cognitive function, and therefore these macrophages were not associated with the observed cognitive function. It was confirmed that this is important for the reduction of Functioning despite other hypertension symptoms.
Researchers were still looking for a source of IL-17 that acts on brain macrophages. Based on previous studies, the researchers' initial hypothesis was that the gut releases IL-17, which travels to the brain through the bloodstream. Once there, a reaction is triggered that damages the ability of the brain's blood vessels to respond appropriately to increased brain activity. However, blocking the ability of cerebral blood vessels to respond to IL-17 only partially reversed the cognitive impairment, suggesting that another source of IL-17 is acting on the brain.
One clue suggests that one layer of the brain's protective layer, known as the dura mater, contains immune T cells that secrete IL-17 and may influence mouse behavior. taken from other recent studies. Using special mice whose cells glow fluorescent green when they make IL-17, the researchers found that high blood pressure increases IL-17 in the dura mater, which is then released into the tissues. Normally, a barrier exists within the brain's protective covering called the meninges to prevent unwanted spillage into the brain. However, in mice with experimentally induced hypertension, this barrier appears to be disrupted, allowing IL-17 to enter the cerebrospinal fluid.
Two additional experiments helped confirm this hypothesis. First, drugs were used to prevent her T cells from moving from the lymph nodes to the meninges. Second, antibodies were used to block the activity of her T cells within the meninges. In both cases, the hypertensive mice recovered cognitive function, suggesting that targeting hyperactive T cells may be a new therapeutic approach worth exploring.
“Taken together, our data suggest that hypertension causes two distinct effects,” Dr. Iadecola said. “One is that IL-17 has an effect on blood vessels, but this seems to be relatively minor. The more prominent central effect is that IL-17 releases IL-17, which has a direct effect on immune cells in the brain. It is caused by cells in the meninges. These immune cells, activated by signaling from the meninges, affect the brain in a way that ultimately causes cognitive impairment.”
Dr. Iadekola and his team are now trying to connect the dots between activation of immune cells in the meninges and decline in cognitive function. Previous works by the group They found that a high-salt diet inhibits the production of the chemical nitric oxide in brain blood vessels, which in turn reduces the accumulation of tau, a toxic protein that forms clumps in neurons affected by Alzheimer's disease. He suggested that there is a relationship between The findings also indicate suppression of nitric oxide production in cerebral blood vessels, and whether this also leads to increased tau production is currently being investigated.
of NINDS’ Mind Your Risks® Campaign This paper highlights the relationship between high blood pressure and brain health (including risk of stroke and dementia), particularly in Black men aged 28 to 45, and provides recommendations to prevent and reduce the impact of high blood pressure on brain health. We offer strategies.
This research was funded by NINDS (NS089323, NS095441, NS123507), the Leon Levy Fellowship in Neuroscience, and the Feil Family Foundation.
nines is the nation's leading funder of research on the brain and nervous system. NINDS' mission is to explore fundamental knowledge about the brain and nervous system and apply that knowledge to reduce the burden of neurological disease.
About the National Institutes of Health (NIH):The nation's medical research agency, NIH, has 27 institutes and centers and is part of the U.S. Department of Health and Human Services. NIH is the primary federal agency that conducts and supports basic, clinical, and translational medical research, investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, please visit www.nih.gov.
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article
Santisteban MM et al. “Meningeal IL-17-producing T cells mediate cognitive impairment in salt-sensitive hypertension” natural neuroscience December 4, 2023. DOI: 10.1038/s41593-023-01497-z
