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Eating too much salt leads to dementia in mice

Eating too much salt can trigger an adaptive immune response in the intestine that leads to reduced resting blood flow in the brain and the development of dementia, at least in mice, according to researchers at Weill Cornell Medicine. Constantino ladecola, Ph.D., and colleagues suggest that their studies are the first to demonstrate how a high-salt diet (HSD) can affect brain perfusion at rest, neurovascular regulation and cognitive function by mechanisms that are independent of any effect on blood pressure. "We found that mice fed HSD developed dementia even when blood pressure did not rise," explains Dr. Ladecola, director of the Feil Family Brain and Mind Research Institute (BMRI) and Professor of Neurology at Anne Parrish Titzell at Weill Cornell. Medicine. "This was surprising because, in humans, the deleterious effects of salt on cognition were attributed to hypertension."

The team's findings also highlight a potential goal to reduce the harmful effects of excessive salt intake in the brain. Nature Neuroscience the team says the findings "unveil a previously uncharacterized brain-gut axis by which eating habits compromise the microvasculature of the brain, leading to impaired brain function and brain function." cognitive impairment ". His published article is entitled Neurovascular and cognitive dysfunction through a TH17 response initiated by the intestine. "

It is estimated that 90% of people in the US consume more salt (sodium chloride) in their diets than the recommended 2300 mg per day., Which is related to cardiovascular diseases, but the studies They also indicate that the harmful effects of eating too much salt extend beyond those in the blood pre A HSD has also been associated with cerebrovascular diseases and strokes, as well as cognitive decline, the authors explain. "These changes in the gut have proven to promote autoimmunity and exacerbate experimental allergic encephalomyelitis, an animal model of multiple sclerosis. "

More recent reports have also suggested that an HSD leads to immune changes in the intestine," resulting in an increased susceptibility of the brain. to autoimmunity, "the authors write." A diet rich in salt induces the accumulation in the intestine of T-helper lymphocytes that produce cytokines. na proinflammatory interleukin-17 (TH17). The involved pathways suppress the anti-inflammatory function of the regulatory T cells. "

To investigate the researchers fed the mice a diet containing 4% or 8% salt, representing an increase of eight and 16 times, respectively, compared to a normal diet of mice.The salt content of the mouse diets was equivalent to the upper end of the salt consumption spectrum in the human diet.After eight weeks, the magnetic resonance imaging studies of the The brains of the mice identified a 28% decrease in cerebral blood flow at rest in the cortex and a 25% decrease in blood flow to the hippocampus, two areas of the brain involved in learning.The HSD also prevented the cells from Brain endothelial cells will produce nitric oxide, which normally acts to relax blood vessels and increase blood flow. or vascular inflammatory that may have caused endothelial dysfunction.

"Similarly, there was no positive regulation of inflammatory genes in brain endothelial cells classified in HSD-fed mice, suggesting that neurovascular dysfunction was not due to a massive inflammatory response in cerebrovascular cells," the authors comment. Encouragingly, the effects of an HSD on cerebral blood flow and endothelial cell function could be reversed, by switching the animals to a normal diet for four weeks.

Normal cognitive function requires a well-regulated blood flow. The researchers found that the mice maintained an HSD dementia developed and worsened in a series of tests, including an object recognition test and a maze test. The change of the animals to a normal diet resulted in improved performance in the novel object recognition test. An HSD also affected the normal nesting behavior, with mice fed with HSD that use less nesting material and that demonstrate a deteriorated capacity of nest formation.

Further investigations showed that animals that eat an HSD developed an adaptive immune response in their bowels and a higher number of TH17 cells, which led to an increase in IL-17 production and circulating levels of IL-17 . IL-17 plays a role in the regulation of immune and inflammatory responses and signals a reduction in the production of nitric oxide by endothelial cells.

Interestingly, the treatment of mice with antibodies directed to IL-17 blocked endothelial dysfunction and cognitive deficits induced by an HSD. Similarly, mice designed to lack IL-17 also did not develop cognitive problems in response to receiving an HSD.

In a final set of experiments, the team treated HSD-fed mice using an inhibitor of the ROCK Y27632 kinase, which acts as preventing the suppression of nitric oxide activity. The treated animals also showed lower circulating levels of IL-17 and improved cognitive and behavioral functions.

"The IL-17-ROCK pathway is an interesting target for future research on the causes of cognitive impairment," suggests Giuseppe Faraco, Ph.D., assistant professor of neuroscience research at BMRI and first author of the study. published by the team. "It seems to counteract the cerebrovascular and cognitive effects of an HSD, and may also benefit people with diseases and conditions associated with elevated levels of IL-17, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and other autoimmune diseases." .

"We have shown that HSD induces a TH17 response in the intestine that leads to an increase in circulating IL-17, which in turn acts on brain endothelial cells to suppress NO endothelial production [nitric oxide] which leads to perfusion reductions and cognitive dysfunction, "the authors conclude. "These data have implications that go beyond the pathology associated with HSD," they say. "Our findings suggest that the IL-17-ROCK pathway is a putative therapeutic target to counteract the harmful cerebrovascular and cognitive effects of HSD and other conditions associated with TH17 polarization.The activation of the TH17-cell-IL-17 pathway it is observed in a number of diseases associated with cerebrovascular dysfunction, including, for example, multiple sclerosis, rheumatoid arthritis, psoriasis and inflammatory bowel disease.To counteract the harmful effects of IL-17-ROCK on the cerebral endothelium would be beneficial to reduce the cardiovascular risk in these conditions. "

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