EXPERT REACTION: A high salt diet may be bad for the brain, mouse study shows

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Eating too much salt might not be good for the brain, at least in mice, according to international researchers who fed mice a diet that was 8-16 times higher in salt than a normal mouse diet. They found the diet could lead to the accumulation of modified tau – a protein associated with conditions that cause dementia, such as Alzheimer’s disease. These mice were less able to navigate mazes and recognise new objects. While this is an extreme version of a high salt diet and further research is needed to apply the results to humans, the researchers say the results indicate a potential pathway that links diet to brain function.

Journal/conference: Nature

Link to research (DOI): 10.1038/s41586-019-1688-z

Organisation/s: Weill Cornell Medicine, USA

Funder: This study was supported by National Institutes of Health grants R37-NS089323 (C.I.) and 1R01-NS095441 (C.I.), by a grant from the Cure Alzheimer’s Fund (G.F. and C.I.) and by a Scientist Development Grant from the American Heart Association (G.F.). Support from the Feil Family Foundation is gratefully acknowledged.

Media Release

From: Springer Nature

Health: High salt intake linked to cognitive decline in mice

A causal link between salt intake and cognitive function in mice is identified in a study published online in Nature this week. The study uncovers how feeding mice an extremely high-salt diet can lead to the accumulation of modified tau — a protein associated with conditions that cause dementia, such as Alzheimer’s disease. Further research is needed to explore whether the results may be translated to humans.

Excessive salt consumption has been linked to cognitive impairment and is a risk factor for dementia. The precise mechanisms that underlie this association are unclear, but vascular dysfunction and the aggregation of tau proteins in neurons are thought to have a role in the development of cognitive impairment. Costantino Iadecola and colleagues find evidence for the latter, identifying a signalling cascade that culminates in increased levels of phosphorylated tau.

Mice that were fed a high-salt diet (8–16 times higher than a normal mouse diet) were less competent at recognizing new objects and struggled with a maze test. The authors show that high salt intake reduces nitric oxide synthesis, which leads to activation of an enzyme (CDK5) that is involved in tau phosphorylation. Cognitive impairment was reversed in mice by restoring nitric oxide production. The authors note that the high-salt diet fed to the mice exceeds the highest reported levels of salt consumption in humans (3–5 times the recommended level of 4–5 grams per day). Nevertheless, the results identify a previously unknown pathway linking dietary habits and cognitive health, which indicates that avoiding high-salt diets could maintain cognitive function.

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Expert Reaction

These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.

Dr Joanna McMillan is an Accredited Practising Dietitian, Registered Nutritionist and Founder of Dr Joanna and Get Lean

What happens in mice does not always happen in humans, but animal studies do provide us with the chance to look for plausible biological mechanisms as is the case here.

We know from human studies that a high salt diet is not good for our health and can indeed impact cognitive function. This may be through increasing the risk of hypertension, but recent studies also point to the same mechanism as reported int his study (i.e. via a deficit of endothelial nitric oxide).

Human diets are more complex than a rodent and in this study, the salt level was extremely high. In human diets however a high salt intake tends to correlate with a poor diet overall. More than ¾ of the salt in an average diet comes from processed foods and not salt added in home cooking or at the table.

It can be difficult therefore to tease apart the key factors – it is likely that high salt, combined with factors such as unhealthy fats, highly refined grains and not enough whole plant food to provide protective factors, are responsible for the dietary effects on cognitive health.

The bottom line is that most Australians are consuming too much salt and this study adds to the building body of evidence to show us why too much salt is harmful.

Last updated: 23 Oct 2019 4:35pm
Declared conflicts of interest:
None declared.
Professor John Funder AC is a Distinguished Scientist from The Hudson Institute, and also from the Centre for Neuroscience at The University of Melbourne

This is a very large and detailed report on mice fed huge amounts of salt, which responded by the equivalents in mice of cognitive impairment.

This decline was associated with too much phosphorylation of tau protein, known to be increased in Alzheimer's disease and in dementia following blood vessel dysfunction, and appears to reflect reduced synthesis of nitric oxide by the endothelial cells lining the blood vessels.

Mercifully, this situation was blocked by giving the long-suffering mice the amino acid arginine, which can be converted to nitric oxide.

The last line of the abstract reads: "Avoidance of an excessive salt intake and maintenance of vascular health may help to stave off the vascular and neurodegenerative pathologies that underlie dementia in the elderly".

This is a pious mantra, given the way that the authors treated the mice. Normal mouse chow contains 0.3 per cent sodium chloride; which would be a high salt intake in humans. The New York mice in question got 8 per cent sodium chloride, despite which, curiously, their blood pressure did not go up; they did, however, eat more and weigh less - not a starter for sensible human weight loss.

The Japanese commonly consume a very high salt diet, despite which they have the world's longest life expectancy. In human diets arginine is rich in nuts, seeds, legumes, meat - and, wait for it, seaweed, which might be the Japanese secret. Any extrapolation from mice on a salt intake of 8 per cent to the human situation may be cute, but it is grossly irresponsible in terms of science.

Almost thirty years ago I wrote a critique of this sort of practice, titled "Physiology, Pharmacology, Toxicology and Strength of Materials", given the cheerful way that experimental animals are subjected to ever-increasing doses of whatever, and the results then piously translated to the human condition.

The report in the venerable journal Nature -  "Dietary salt promotes cognitive impairment through tau phosphorylation", despite its provenance, should be considered somewhere between Toxicology and Strength of Materials.

Last updated: 23 Oct 2019 1:00pm
Declared conflicts of interest:
None declared.
Dr Evangeline Mantzioris is the Program Director of Nutrition and Food Sciences at the University of South Australia

We already know that a diet high in salt is known to be an independent risk factor for stroke and dementia in humans. It appears that this is mediated by the high salt diets causing damage to the small blood vessels in the brain which reduces blood flow to the brain. 

This reported study from Faraco and colleagues published in Nature has shown mice fed high salt diets had damage to the ‘tau-protein function’ in the brain. Changes to the way tau-protein functions in the brain has been seen in diseases such as Alzheimer’s.

This study was an experimental study so we do have a direct cause and effect, that is the high salt diets did cause changes to the tau-protein in the brains of the mice. However, there are a couple of things we should note.

Firstly, the amount of salt that was given to these mice does exceed the highest reported intake in humans, which is 3-5 times the recommended level of salt intake (12.5-20g/day).

Secondly, while this mouse model does provide a good biological equivalence to the human brain, we cannot with certainty say the same effect would happen in humans. 

Despite these, this is a very important piece of research as it is the first time that a dietary component, salt, has been shown to cause blood vessel and tau-protein damage in the brain.

It contributes to the evidence base which tells us we should be reducing the amount of added salt (at the processing level, cooking and at the dinner table) that we have in our diet and focus on consuming a healthy balanced diet containing breads and cereals, legumes, fruits and vegetables and with minimal amounts of processed foods.

Last updated: 23 Oct 2019 12:57pm
Declared conflicts of interest:
None declared.
Dr Lauren Ball is an NHMRC Early Career Research Fellow at the Menzies Health Institute Queensland, Griffith University.

This is another example that shows the way we eat influences our health and ability to live well.

It reinforces the need for nutrition to be a fundamental part of our health system, including the regular contact we have with doctors, nurses and allied health professionals across our life span.

Last updated: 23 Oct 2019 12:56pm
Declared conflicts of interest:
None declared.
Professor Clare Collins is an NHMRC Senior Research Fellow, Director of Research in the School of Health Sciences, and Deputy Director of Priority Research Centre in Physical Activity & Nutrition at The University of Newcastle

This study in mice found that feeding them a diet very high in salt led to poorer performance at recognising new objects and in finding their way during a maze test.

The researchers identified a new mechanism leading to a buildup of a protein called modified tau that is associated with the development of dementia, and Alzheimer’s disease in particular.

This mouse study is important and will help to provide the basis for looking at whether high salt diets increase dementia risk in humans by similar mechanisms.

They fed the mice in the experiments 8-16 times more salt than is typical for a mouse diet. This is much higher than even the highest reported salt consumption in adult humans, which is up to 3-5 times more than the suggested dietary target of 5 grams or one teaspoon of salt per day.

We know that high salt intakes increase blood pressure, a risk factor for dementia. There is also human research suggesting high salt intakes impair some brain functions.

The current study reinforces the need for Australians to avoid adding salt to meals, salty snacks and high-salt processed foods.

By boosting your intake of a variety of vegetables and fruits, which are high in potassium, some adverse effects of high salt intake can be reduced. This will also improve blood pressure levels and help artery walls to remain flexible, assisting with blood flow to your brain.

Last updated: 23 Oct 2019 12:54pm
Declared conflicts of interest:
None declared.
Dr Rosemary Stanton OAM, Nutritionist, Visiting Fellow, School of Medical Sciences, University of New South Wales

There’s no shortage of evidence that too much salt is not conducive to health. Its effects on blood pressure are well established and a high salt diet also increases the risk of renal disease and stomach cancer. A number of studies also note changes in brain tissue caused by a high salt diet.

This latest study published in Nature takes a fresh look at why a high salt intake may also play a role in impairing brain function. Using mice, the researchers have unveiled some reasonably complicated biochemistry. However the resulting message is clear: too much salt harms the body, including the brain. And that impacts on cognitive function.

In working out the possible mechanism as to why salt harms the brain, the mice were given very large doses – 8-16 times the usual salt in normal chow for these animals. Translated into human terms, it’s about twice what the average Australian consumes. Note however, that the average Australian intake of salt is approximately twice the maximum intake recommended by the World Health Organisation.

The take home message is that this study gives extra strength to the need to cut back on salt. And with about 80 per cent of our salt coming from processed and ready-prepared foods, this is yet another reason for us to return to fresh foods, or to seek out those prepared without salt.

Supermarkets stock canned products such as chickpeas, tomatoes and fish without added salt. By choosing rolled oats and turning them into porridge or muesli you can avoid the salt in prepared breakfast cereals. 

With any processed product, check the salt content. Low salt products have sodium levels of no more than 120mg sodium/100g.

Last updated: 23 Oct 2019 12:52pm
Declared conflicts of interest:
None declared.

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