High levels of dietary salt can activate a pathway in the brain to cause cognitive impairment, according to a new study. The paper, which was published in Nature, shows that this effect is not due to a loss in blood flow to the brain as originally thought, but rather to clumps of a protein linked to several forms of dementia in humans. The research was funded by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.
"This study continues the important story of the effects of a high-salt diet on the brain," said Jim Koenig, Ph.D., program director at NINDS. "This work in mice reveals a new target for therapies aimed at brain blood vessel dysfunction."
In a previous research study, scientists led by Costantino Iadecola, M.D., director and chair of the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine in New York City, showed that mice that ate a diet high in sodium began to show symptoms of dementia due to changes that occurred in the gut. The diet also produced a drop in the flow of blood to the brain, which they thought would be the cause of the dementia symptoms. However, when they looked more closely, they found instead that a buildup of a protein called tau in the brain was the cause.
"This result was completely unexpected," said Dr. Iadecola. "We knew that a high-salt diet produced dementia-like symptoms in mice, and we went in thinking the culprit would be reduced blood flow to the brain. It turned out that wasn't the case at all."
The original link found between high salt diets and brain blood flow was a decrease in the production of nitric oxide (NO) in cells making up blood vessels in the brain, caused by a reduction in the function of the enzyme eNOS. Blood flow in the brain increases when NO is present; however, NO generated from blood vessel cells has several other functions in the brain. These include being part of a molecular pathway connected to tau that, in the absence of sufficient NO, can modify tau protein in a way that causes it to clump together to form aggregates. In a family of diseases called tauopathies, it is these tau aggregates that interfere with the proper function of brain cells, which can lead to cognitive impairment and eventually dementia. When mice consumed the high-salt diet in this study, their brains also showed evidence of tau aggregates that coincided with reduced cognitive abilities.
The researchers further showed that tau was the important factor behind these effects by studying mice that had their gene for tau deleted. These mice showed a similar drop in brain blood flow, but because they could not make tau protein, they did not form tau aggregates, nor did they show a decrease in their cognitive abilities. Similar results were observed with an antibody against tau.
"The take-home message here is that is that while there is a reduction in blood flow to the brains of mice that eat a high-salt diet, it really is tau that is causing the loss in cognitive abilities. The effect of reduced flow really is inconsequential in this setting," said Dr. Iadecola.
He noted this result could have been predicted. After eating a high amount of sodium, the mice had about a 25% decrease in blood flow. This drop is similar to what is seen in people after drinking a cup of coffee. Evidence suggests it actually takes about a 50% drop before the brain can no longer compensate and cognitive effects are seen.
Although Dr. Iadecola points out that the salt content consumed by the mice in this study is eight to 16 times higher than normal and is likely to be more than a person would consume in a single day, their findings provide important links between diet, the blood vessels of the brain, and cognition.
"Our results highlight the importance of thinking beyond blood flow when treating disorders affecting the brain's blood vessels," said Dr. Iadecola.
This work was supported by NINDS (NS089323, NS095441), the Cure Alzheimer's Fund, the American Heart Foundation, and the Feil Family Foundation.
Faraco G. et al. Dietary salt promotes cognitive impairment through tau phosphorylation. Nature. October 23, 2019. DOI: 10.1038/s41586-019-1688-z
NINDS is the nation's leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.
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