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High Salt Diet Produces Dementia: Mouse Study

Summary: Researchers reveal high salt intake reduces resting cerebral blood flow and can contribute to dementia in mice.

Source: Weill Cornell Medicine.

A high-salt diet reduces resting blood flow to the brain and causes dementia in mice, according to a new study by scientists from Weill Cornell Medicine.

The study, published Jan. 15 in Nature Neuroscience, is the first to unveil a gut-brain connection linking high dietary salt intake to neurovascular and cognitive impairment. The findings illuminate a potential future target for countering harmful effects to the brain caused by excess salt consumption.

“We discovered that mice fed a high-salt diet developed dementia even when blood pressure did not rise,” said senior author Dr. Costantino Iadecola, director of the Feil Family Brain and Mind Research Institute (BMRI) and the Anne Parrish Titzell Professor of Neurology at Weill Cornell Medicine. “This was surprising since, in humans, the deleterious effects of salt on cognition were attributed to hypertension.”

A vast majority, about 90 percent of American adults, consume more dietary sodium than the recommended 2,300 mg per day.

The mice were given food containing 4 percent or 8 percent salt, representing an 8- to 16-fold increase in salt compared to a normal mouse diet. The higher level was comparable to the high end of human salt consumption. After eight weeks, the scientists examined the mice using magnetic resonance imaging. The mice showed marked reductions in resting cerebral blood flow in two areas of the brain involved in learning and memory: 28 percent decrease in the cortex and 25 percent in the hippocampus.

The scientists discovered that an impaired ability of cells lining blood vessels, called endothelial cells, reduced the production of nitric oxide, a gas normally produced by the endothelial cells to relax blood vessels and increase blood flow. To see if the biological effects of a high-salt diet could be reversed, Dr. Iadecola and colleagues returned some mice to a regular diet for four weeks and found that cerebral blood flow and endothelial function returned to normal.

Rodents that only ate the high-salt diet developed dementia, performing significantly worse on an object recognition test, a maze test and nest building–a typical activity of daily living for mice, spending less time building nests and using much less nesting material than normal mice.

Next, the scientists performed several experiments to understand the biological mechanisms connecting high salt intake with dementia. They discovered that the mice developed an adaptive immune response in their guts, with increased activity of a subset of white blood cells that play an important role in the activity of other immune cells. The increase in those white blood cells, T helper lymphocytes called TH17, boosted the production of a protein called interleukin 17 (IL-17) that regulates immune and inflammatory responses, causing a reduction in the production of nitric oxide in endothelial cells.

Image shows intestinal slices.

White blood cells that produce a protein called IL-17 (green) accumulate in large numbers in the small intestine of mice fed a high-salt diet for eight weeks (right), compared with mice fed a normal diet. This magnified image shows cells in a part of the intestinal layer that absorbs digested food and protects against infection. NeuroscienceNews.com image is credited to The Iadecola Lab.

In a final experiment, the scientists treated the mice with a drug known to prevent the suppression of nitric oxide activity, called ROCK inhibitor Y27632. The drug reduced circulating levels of IL-17 and the mice showed improved behavioral and cognitive functions, said Dr. Iadecola, who is on the strategic advisory board and receives a consulting fee from Broadview Ventures Inc. Broadview Ventures Inc. was created by the board of the Foundation Leducq Trust, the supporting trust of Foundation Leducq.

“The IL-17-ROCK pathway is an exciting target for future research in the causes of cognitive impairment,” said Dr. Giuseppe Faraco, assistant professor of research in neuroscience in the BMRI and first author of the study. “It appears to counteract the cerebrovascular and cognitive effects of a high-salt diet, and it also may benefit people with diseases and conditions associated with elevated IL-17 levels, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and other autoimmune diseases.”

About this neuroscience research article

Funding: The study was supported by two grants from the National Institutes of Health (R37-NS089323 and 1R01-NS095441), a Scientist Development Grant from the American Heart Association and a network grant from Fondation Leducq.

Source: Jen Gundersen – Weill Cornell Medicine
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to The Iadecola Lab.
Original Research: Abstract for “Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response” by Giuseppe Faraco, David Brea, Lidia Garcia-Bonilla, Gang Wang, Gianfranco Racchumi, Haejoo Chang, Izaskun Buendia, Monica M. Santisteban, Steven G. Segarra, Kenzo Koizumi, Yukio Sugiyama, Michelle Murphy, Henning Voss, Joseph Anrather & Costantino Iadecola in Nature Neuroscience. Published online January 15 2018 doi:10.1038/s41593-017-0059-z

Cite This NeuroscienceNews.com Article

Weill Cornell Medicine “High Salt Diet Produces Dementia: Mouse Study.” NeuroscienceNews. NeuroscienceNews, 16 January 2018.
<http://neurosciencenews.com/dementia-high-salt-diet-8323/>.
Weill Cornell Medicine (2018, January 16). High Salt Diet Produces Dementia: Mouse Study. NeuroscienceNews. Retrieved January 16, 2018 from http://neurosciencenews.com/dementia-high-salt-diet-8323/
Weill Cornell Medicine “High Salt Diet Produces Dementia: Mouse Study.” http://neurosciencenews.com/dementia-high-salt-diet-8323/ (accessed January 16, 2018).

Abstract

Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response

A diet rich in salt is linked to an increased risk of cerebrovascular diseases and dementia, but it remains unclear how dietary salt harms the brain. We report that, in mice, excess dietary salt suppresses resting cerebral blood flow and endothelial function, leading to cognitive impairment. The effect depends on expansion of TH17 cells in the small intestine, resulting in a marked increase in plasma interleukin-17 (IL-17). Circulating IL-17, in turn, promotes endothelial dysfunction and cognitive impairment by the Rho kinase–dependent inhibitory phosphorylation of endothelial nitric oxide synthase and reduced nitric oxide production in cerebral endothelial cells. The findings reveal a new gut–brain axis linking dietary habits to cognitive impairment through a gut-initiated adaptive immune response compromising brain function via circulating IL-17. Thus, the TH17 cell–IL-17 pathway is a putative target to counter the deleterious brain effects induced by dietary salt and other diseases associated with TH17 polarization.

“Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response” by Giuseppe Faraco, David Brea, Lidia Garcia-Bonilla, Gang Wang, Gianfranco Racchumi, Haejoo Chang, Izaskun Buendia, Monica M. Santisteban, Steven G. Segarra, Kenzo Koizumi, Yukio Sugiyama, Michelle Murphy, Henning Voss, Joseph Anrather & Costantino Iadecola in Nature Neuroscience. Published online January 15 2018 doi:10.1038/s41593-017-0059-z

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