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A High-Salt Diet Promotes Phosphorylated Tau and Cognitive Decline in Mice

Article In Brief

Researchers fed experimental mice a high-salt diet for two to three months and observed the formation of increased toxic tau and significant cognitive decline. The investigators suggest that reducing salt intake, in concert with other measures to promote brain health, could ultimately be an important modifier in reducing dementia.

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Bypass the salt, please—or at least, that may be one takeaway from a new study that found a high-salt diet fed to middle-aged lab animals triggered the production of phosphorylation tau protein, which directly led to cognitive impairments.

“The study offers the first evidence that diet can increase the formation of toxic tau and in turn impact the same kinds of memory problems seen in dementia,” said the study's first author, Costantino Iadecola, MD, the Anne Parrish Titzell professor of neurology and director and chair of the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine.

In the paper, published in the October 23 online edition of Nature, Dr. Iadecola and colleagues reported that reducing salt in the diet stopped these molecular events and the memory tests improved.

The amount of salt tested in the study was exceedingly high, comparable to salt levels used in Japan in the 1960s, but, it is an “important proof of principle,” Dr. Iadecola told Neurology Today.

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“We now have evidence for a direct interaction between endothelial and neuronal cells. Just the idea that there is this communication opens up important avenues for interventions. Endothelial cells are more accessible than neuronal tissue. This is one more reason to be careful about consuming too much salt.”—DR. ZVONIMIR KATUSIC

The scientists at Weill Cornell Medicine who conducted the study said that reducing dietary salt, in concert with other measures to promote brain health, could ultimately be an important modifier in reducing dementia. These surprising results come on the heels of another study Dr. Iadecola and his colleagues published last year in Nature Neuroscience. At two to three months, the equivalent of early adulthood in humans, they began feeding mice a diet with eight to 16 times the salt content of normal mouse chow. The high-salt diet continued for two to three months. The research team observed significant cognitive decline and their studies led them to suspect the involvement of the cerebral microvascular system.

Dr. Iadecola explained that salt sparked a molecular cascade: An adaptive immune response started in the gut, triggering the expansion of IL17-producing lymphocytes and increasing circulating levels of IL17, which, in turn, reached endothelial cells in brain microvessels and inhibited endothelial nitric oxide production. This impaired endothelial vasoactivity led to a 25 percent reduction in cerebral blood flow. Four weeks after the animals returned to their normal diet, all of the effects of the high-salt diet disappeared. Nitric oxide levels were normal again, and so were the changes in the blood vessels. Moreover, the behavioral tests were normal, as well.

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“We thought it was the reduction of blood flow. But it was really an accumulation of phosphorylated tau. Endothelial nitric oxide regulates tau phosphorylation.”—DR. GIUSEPPE FARACO

“How this impacts lifelong cognitive changes is something that scientists need to explore. Additionally, this study also provides a new potential target for the reversal of learning and memory deficits.”

—DR. JIM I. KOENIG

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“This study provides important insights into how a high-salt diet changes cerebral blood flow and induces a series of biochemical reactions that culminate in a toxic species of tau and cognitive decline.”—DR. LI-HUEI TSAI

The study authors had thought that the reduced blood flow compromises oxygen stores, which could have an effect on cognitive function. It was an intriguing set of molecular events and the scientists were ready to leave it at that. But something in the medical literature made Dr. Iadecola and Giuseppe Faraco, MD, PhD, assistant professor of research in neuroscience at Weill Cornell and the first author of the study, wonder whether this really was a cause-effect event, or the only one. They knew from other studies in the literature that endothelial nitric oxide regulates tau phosphorylation. Maybe the problem wasn't just the blood flow, after all, they thought.

Study Design, Findings

The research team designed the new set of experiments—first to test whether a high-salt diet led to phosphorylation of tau, and then to figure out how that occurs. The investigators fed male mice (and later female mice) a normal diet or a high-salt diet, as they did in their previous study. After three months, they used Western blot assays to look for phosphorylated tau (p-tau). They found an increase in p-tau in the hippocampus and the neocortex. Total tau did not change and no tangles formed, but there was increased insoluble tau. They used several tau antibodies to confirm the finding. The animals began to have cognitive problems about two months into the high-salt diet. This occurred without evidence of neuronal or white matter damage, or changes in astrocytes, microglia or pericytes.

Mice began having trouble recognizing novel objects and couldn't find their way around the Barnes maze. The more p-tau they measured, the more cognitive problems mice had. Insoluble tau was accumulating in the brains of these animals, both male and female.

To figure out what was going on, the scientists treated the animals with a nitric oxide precursor, L-arginine. This prevented the cognitive problems and reduced p-tau, said Dr. Iadecola. The treatment had no effect on reducing the circulating cytokine, IL-17, and blood flow was still reduced. They also tested the effects in endothelial nitric oxide knockout mice fed a normal and high-salt diet. P-tau levels were increased in the knockout mice fed a normal diet but were not increased further when fed a salt-rich diet. Again, this was showing the importance of endothelial nitric oxide deficiency and the development of p-tau.

Studies of the pathways downstream of endothelial nitric oxide demonstrated that the increased p-tau resulted from activation of the enzyme cyclin-dependent kinase, Cdk5, known to regulate tau phosphorylation. Indeed, a Cdk5 inhibitor blocked p-tau accumulation and it also prevented the cognitive decline.

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“The study offers the first evidence that diet can increase the formation of toxic tau and in turn impact the same kinds of memory problems seen in dementia.”—DR. COSENTINO IADECOLA

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“The question is how do we translate this finding to humans? This was a high-dose model. How much salt can be safely used without causing cerebral blood flow problems? The data are compelling enough that we need to ask these questions and get answers as soon as possible.”—DR. RUDOLPH TANZI

The last set of experiments tested tau-null mice and an antibody against tau to understand whether it is p-tau or the reduction in blood flow that triggers cognitive decline in animals on a high-salt diet. Interestingly, middle-aged tau-null mice fed a high-salt diet were not cognitively impaired, even though they too had reduced blood flow. Similarly, wild-type mice given tau antibody with their high-salt diet in the last four weeks of their 12-week diet showed significant improvements in cognitive function despite the reduced blood flow.

“We thought it was the reduction of blood flow,” explained Dr. Faraco. “But it was really an accumulation of phosphorylated tau. Endothelial nitric oxide regulates tau phosphorylation.”

The scientists are now checking to see whether tau was cleared from the brains of the animals after the high-salt diet was stopped. They are now designing a study adding sweet and salty food to see whether the effects are different.

Expert Commentary

“This is a very exciting paper,” said Zvonimir Katusic, MD, PhD, professor of pharmacology and anesthesiology at the Mayo Clinic in Rochester, MN, whose research has focused on cerebral vasculature in experimental models of stroke and Alzheimer's disease. “The field has focused on cerebral blood flow and perfusion but it is becoming apparent that endothelial cells may affect neuronal function independently of their role in controlling blood flow.”

“This is an elegant demonstration that nitric oxide derived from endothelial cells is important for the regulation of tau phosphorylation,” Dr. Katusic said. “We now have evidence for a direct interaction between endothelial and neuronal cells. Just the idea that there is this communication opens up important avenues for interventions. Endothelial cells are more accessible than neuronal tissue. This is one more reason to be careful about consuming too much salt.”

“Given that we all love salt it is important to know what these findings mean for people,” said Rudolph Tanzi, PhD, professor of neurology at Massachusetts General Hospital and Harvard Medical School. “The question is how do we translate this finding to humans? This was a high-dose model. How much salt can be safely used without causing cerebral blood flow problems? The data are compelling enough that we need to ask these questions and get answers as soon as possible.”

“We know that neuroinflammation causes oxidative stress and this can lead to the buildup of toxic tau,” he added. Interestingly, Dr. Tanzi and his colleagues did a genome-wide association study years ago and found a signal on chromosome 3, in the area where the IL-17 gene resides.

“This study [underscores] the importance of the impact of environmental and dietary factors on the brain,” said Jim I. Koenig, PhD, program director for the stroke program in the neural environment portfolio at the National Institute for Neurological Disorders and Stroke, which funded the Nature study.

“This [study] demonstrates for the first time that what you eat can impact cognition that is directly related to an inflammatory process associated with the tau protein. Maybe tau is a critical element and we need to think about the consequences of a high-salt diet on cognition.”

“We also have no idea what a lifetime of using too much salt can do to the brain,” Dr. Koenig said. “How this impacts lifelong cognitive changes is something that scientists need to explore. Additionally, this study also provides a new potential target for the reversal of learning and memory deficits.”

Li-Huei Tsai, PhD, professor in the department of brain and cognitive sciences at Massachusetts Institute of Technology and director of the Picower Institute for Learning and Memory, said: “This study provides important insights into how a high-salt diet changes cerebral blood flow and induces a series of biochemical reactions that culminate in a toxic species of tau and cognitive decline.”

Disclosures

Dr. Iadecola serves on the scientific advisory board of Broadview Ventures. Drs. Tanzi, Faraco, Koenig, and Tsai reported no competing interests.

Link Up for More Information

• Faraco G, Hochrainer K, Segarra SG, et al. Dietary salt promotes cognitive impairment through tau phosphorylation https://www.nature.com/articles/s41586-019-1688-z. Nature 2019; Epub 2019 Oct 23.
    • Faraco G, Bread D, Garcia-Bonilla L, et al. Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response https://www.nature.com/articles/s41593-017-0059-z. Nat Neurosci 2018;21(2):240–249.
    • Scarmeas N, Anastasiou C A, Yannakoulia M. Nutrition and prevention of cognitive impairment https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(18)30338-7/fulltext. Lancet Neurol 2018;17:1006–1015.
    • Kendig MD, Morris MJ. Reviewing the effects of dietary salt on cognition: Mechanisms and future directions http://apjcn.nhri.org.tw/server/APJCN/28/1/6.pdf. Asia Pac J Clin Nutr 2019;28(1):6–14.