Mice fed a very high-salt diet showed accumulation of a protein in the brain linked with Alzheimer’s disease and other dementias

A diet high in salt is known to be a risk factor for high blood pressure, which in turn raises the risk of stroke and other health problems. Research has suggested that high salt intake may also be a risk factor for declining brain function with age. However, the mechanisms responsible for this link aren’t understood.
Previous studies suggested that high levels of salt in the diet can cause immune changes in the gut that lead to reduced blood flow in the brain and impaired cognition. In previous work, a team led by Dr. Costantino Iadecola at Weill Cornell Medicine found that mice fed a high-salt diet had reduced functioning of an enzyme called eNOS, which produces nitric oxide (NO).
NO helps direct blood vessels to relax, thereby increasing blood flow. Mice with a reduction in NO from the high-salt diet had reduced blood flow to the brain. These mice had trouble performing a standard set of cognitive tasks.
But the researchers suspected that the amount of reduced blood flow seen in these experiments wasn’t enough to directly affect cognition. In their new study, they explored how changes in the brain caused by a high-salt diet—and the resulting lowered NO production—might affect thinking and memory.
The team fed mice a very high-salt diet for 12 to 36 weeks. The mice underwent tests of cognitive function, and their brains were examined for molecular changes. The work was funded in part by NIH’s National Institute of Neurological Disorders and Stroke (NINDS). Results were published on October 23, 2019, in Nature.
The researchers found that high levels of dietary salt caused a chemical change to a protein called tau. This change—phosphorylation—can cause tau to clump together in the brain. Clumps of tau are linked with some dementias, such as Alzheimer’s disease.
As in their previous study, the team found that mice fed the high-salt diet had trouble recognizing novel objects and navigating through a maze. Mice with more phosphorylated tau in their brains had lower performance on these cognitive tasks.
When the mice were fed a high-salt diet supplemented with a compound that boosts NO production, they were protected against the accumulation of phosphorylated tau.
To confirm the link between salt intake, tau, and cognitive decline, the researchers fed the high-salt diet to mice that lacked tau. Those mice were protected from cognitive decline on the high-salt diet, even though they had reduced blood flow to the brain. Similar results were seen when tau was blocked in normal mice.
Further molecular studies showed that the effects of high salt on tau phosphorylation were mediated through NO levels, not through changes in blood flow.
“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,” Iadecola says.
The amount of salt fed to the mice was 8 to 16 times higher than that found in normal mouse chow. Most people wouldn’t approach such a high level in their diet. But the findings reveal a mechanism that might link high salt intake with reduced brain functioning. The results suggest that therapies targeting blood flow to the brain may not be enough to counter cognitive decline.

In Down Syndrome mouse model, scientists reverse intellectual deficits with drugs

In a surprising finding using the standard animal model of Down syndrome (DS), scientists were able to correct the learning and memory deficits associated with the condition -- the leading genetic cause of cognitive disability and the most frequently diagnosed chromosomal disorder in the U.S. -- with drugs that target the body's response to cellular stresses.
In a study published Nov. 14, 2019 in the journal Science, a team led by researchers at UC San Francisco and Baylor College of Medicine show that some of the intellectual impairments associated with DS may be traced to altered protein production in a region of the brain called the hippocampus, which is central to learning and long-term memory formation.
But in the so-called Ts65Dn mouse, engineered to capture genetic, behavioral, and cognitive features of human Down syndrome, these changes can be undone. When the researchers administered drugs that target one of the cell's key stress response pathways, they were able to bring protein levels back to normal, which caused the cognitive deficits typical of the Ts65Dn mouse to vanish.
Although the cognitive features of DS have generally been thought of as irreversible, the researchers say, these findings indicate that it may be possible to improve cognitive function in human DS using similar compounds.
A New Approach for Studying Down Syndrome Because DS is caused by an extra copy of chromosome 21, scientists have generally studied the disease through the lens of genetics, focusing primarily on ways in which the superfluous chromosome disrupts normal gene activity. But in the new study, rather than restricting their efforts to genes and chromosomes, the scientists trained their sights on the largely unexplored role of "proteostasis" -- a technical term for the cell's protein manufacturing and quality control machinery -- in DS.
"The vast majority of the field has been focusing on individual genes on chromosome 21 to figure out which ones are causally related to Down syndrome and its pathologies. Our approach was different. We were trying to uncover a link between proteostasis defects and DS," said Peter Walter, PhD, professor of biochemistry and biophysics at UCSF and co-senior author of the new study.
Walter spearheaded the new study with collaborator Mauro Costa-Mattioli, PhD, a professor of neuroscience at Baylor College of Medicine who is currently a visiting professor in Walter's lab thanks to a UCSF Presidential Chair Award.
To identify proteostasis problems that might contribute to DS, the researchers turned to a common mouse model that captures most of the chromosomal, developmental and cognitive abnormalities that define the human version of the syndrome.
Using polysome profiling, a technique that allows scientists to take a detailed snapshot of the cell's protein factories in action, the researchers found that up to 39 percent less protein was being produced in the hippocampus of DS mice, prompting them to ask why extra copies of genes could lead to a decline in protein production.
Stress Response to Blame for Cognitive Impairments Seen in Down Syndrome The researchers discovered that hippocampal cells in DS mice had activated what's known as the integrated stress response (ISR), a biological circuit that detects when something's awry -- the presence of an extra chromosome, for example, in the case of DS -- and engages a protective response that activates machinery to tamp down protein production.
"The cell is constantly monitoring its own health. When something goes wrong, the cell responds by making less protein, which is usually a sound response to cellular stress. But you need protein synthesis for higher cognitive functions, so when protein synthesis is reduced, you get a pathology of memory formation," said Walter.
Backing up these results, the scientists also found that the ISR was also activated in postmortem samples of brain tissue from people with DS. And by a stroke of pure luck, the researchers were able to obtain a tissue sample from a person with DS in whom some cells carried the expected third copy of chromosome 21, while others were genetically normal -- the ISR, however, was only active in the cells with the extra chromosome.
Taken together, these findings strongly suggest that the ISR is involved in, and perhaps even responsible for, certain DS symptoms.
Though the ISR can be activated by four different enzymes, the scientists found that only one of them, named PKR, was involved in activating the ISR in hippocampal cells in DS. By blocking the activity of PKR they were able to prevent ISR activation and reverse the declines in protein production that had been observed in the brains of DS mice. But even more impressive, the researchers found that blocking the ISR significantly improved cognitive function in these mice as well.
Blocking the Stress Response Improves Memory and Learning The researchers used three different approaches to dial down ISR activity -- deleting the PKR gene, using a drug that suppresses PKR activity, and finally, using a safe, well-studied drug called ISRIB that activates protein-manufacturing machinery that competes directly with the ISR's efforts to shut off protein production. All three approaches yielded a marked improvement in cognition, as demonstrated by two different memory and learning tests.
Importantly, these changes were physiological as well as behavioral. DS mice that were given ISR inhibitors showed improved function at synapses, sites between nerve cells where changes associated with learning take place. In fact, after ISR activity was blocked, the brains of DS mice were transmitting fewer of the inhibitory signals that can make it harder for the brain to learn and form new long-term memories.
Though the results of the study were extremely promising, Walter cautions that much more in this area remains to be studied. Still, the findings are an important first step towards finding therapies that could improve the lives and overall health of people living with DS, a condition that has generally been considered untreatable.
"We started with a situation that looked hopeless," Walter said. "Nobody thought anything could be done. But we may have struck gold."

Ketogenic diet helps tame flu virus \

A high-fat, low-carbohydrate diet like the Keto regimen has its fans, but influenza apparently isn't one of them.
Mice fed a ketogenic diet were better able to combat the flu virus than mice fed food high in carbohydrates, according to a new Yale University study published Nov. 15 in the journal Science Immunology.
The ketogenic diet -- which for people includes meat, fish, poultry, and non-starchy vegetables -- activates a subset of T cells in the lungs not previously associated with the immune system's response to influenza, enhancing mucus production from airway cells that can effectively trap the virus, the researchers report.
"This was a totally unexpected finding," said co-senior author Akiko Iwasaki, the Waldemar Von Zedtwitz Professor of Immunobiology and Molecular, Cellular and Developmental Biology, and an investigator of the Howard Hughes Medical Institute.
The research project was the brainchild of two trainees -- one working in Iwasaki's lab and the other with co-senior author Visha Deep Dixit, the Waldemar Von Zedtwitz Professor of Comparative Medicine and of Immunobiology. Ryan Molony worked in Iwasaki's lab, which had found that immune system activators called inflammasomes can cause harmful immune system responses in their host. Emily Goldberg worked in Dixit's lab, which had shown that the ketogenic diet blocked formation of inflammasomes.
The two wondered if diet could affect immune system response to pathogens such as the flu virus.
They showed that mice fed a ketogenic diet and infected with the influenza virus had a higher survival rate than mice on a high-carb normal diet. Specifically, the researchers found that the ketogenic diet triggered the release of gamma delta T cells, immune system cells that produce mucus in the cell linings of the lung -- while the high-carbohydrate diet did not.
When mice were bred without the gene that codes for gamma delta T cells, the ketogenic diet provided no protection against the influenza virus.
"This study shows that the way the body burns fat to produce ketone bodies from the food we eat can fuel the immune system to fight flu infection," Dixit said.

New finding offers possibility for preventing age-related metabolic disease

A study by researchers at Yale has uncovered why belly fat surrounding organs increases as people age, a finding that could offer new treatment possibilities for improving metabolic health, thereby reducing the likelihood for diseases like diabetes and atherosclerosis that stem from inflammation.
Led by Dr. Vishwa Deep Dixit, the Waldemar Von Zedtwitz Professor of Comparative Medicine and of Immunobiology, the study was published Nov. 15 in Cell Metabolism.
Previous work found that as people age, their body's ability to generate energy by burning the belly fat is reduced. Consequently, fat that surrounds the internal organs increases in the elderly. Dixit's lab had found that the immune cells necessary to the fat-burning process, called macrophages, were still active but their overall numbers declined as belly fat increased with aging.
This latest study found that something else is happening as well. Adipose B cells in belly fat unexpectedly proliferated as animals aged, contributing to increased inflammation and metabolic decline. "These adipose B cells are a unique source of inflammation," Dixit said, "normally the B cells produce antibodies, and defend against infection. But with aging, the increased adipose B cells become dysfunctional, contributing to metabolic disease."
When they are working correctly, Dixit said, some B cells expand as needed to protect the body from infection, and then contract to baseline. But with aging, they don't contract in belly fat.
"This predisposes an animal to diabetes and metabolic dysfunction like inability to burn fat," he said. Dixit theorizes that this ongoing expansion may be due to increased human life expectancy - a pushing of the body's cells beyond their evolutionary limits. "Several mechanisms in the body are not selected for longevity," he said.
Researchers discovered that adipose B cells expand by receiving signals from nearby macrophages. Relatedly, they found that by reducing the macrophage signal and by removing adipose B cells, they could reverse the expansion process, and protect against age-induced decline in metabolic health.
This could lead to exciting possibilities for repurposing drugs to target these dysfunctional adipose B cells for improved health outcomes and to protect against metabolic disease, Dixit said. One drug, called cytokine IL-1B, reduces one of the small proteins driving this process and is currently used to protect against heart disease. "It's important to study whether reducing this cytokine in the elderly can lower B cell expansion in belly fat," Dixit said.
He added that there are also immunotherapy drugs that neutralize B cells that are used in certain cancers. These, too, could be tested for their effectiveness in reducing metabolic disease in elderly people, Dixit said.

Sugar binges increase risk of inflammatory bowel disease

Short-term increases in sugar consumption could increase the risk of inflammatory bowel disease and have a significant impact on our health, a new study out of the University of Alberta suggests.
In a study published in Scientific Reports, U of A researchers found that mice had an increased susceptibility to chemically induced colitis and more severe symptoms after only two days of a high-sugar diet compared with those eating a balanced diet.
Karen Madsen, who specializes in diet and its effects on inflammatory bowel disease, said the results echo what many patients with colitis have been saying for a long time: small changes in their diet can make their symptoms flare up.
"It's been previously shown that the type of diet that you are on can change your susceptibility to disease," said Madsen, who led the new study.
"We wanted to know how long it takes before a change in diet translates into an impact on health. In the case of sugar and colitis, it only took two days, which was really surprising to us. We didn't think it would happen so quickly."
What could drive such a significant change in such a short time? It turns out it's all about gut bacteria and the impact food has on them.
Fibre-rich foods act as fuel for the "good" bacteria that live in the gut and produce short-chain fatty acids, which are critical for an efficient immune response. Eating high-sugar diets and decreasing intake of fibre feeds "bad" microbes, such as E. coli, that are associated with inflammation and a defective immune response.
Madsen's study showed that the mice on the high-sugar diet had greater intestinal tissue damage and a defective immune response. These problems were alleviated when their diet was supplemented with short-chain fatty acids normally produced by good bacteria.
"Surprisingly, our study shows that short-term sugar consumption can really have a detrimental impact, and so this idea that it's OK to eat well all week and indulge in junk food on the weekend is flawed," Madsen explained.
Followup studies could pave the way to possibly using short-chain fatty acids as dietary supplements, she noted.
"Changing someone's diet is one of the hardest things to do, even if you tell them that it will fix their health problems," she said.
"People want to eat what they want to eat, so short-chain fatty acids could possibly be used as supplements to help protect people against the detrimental effects of sugar on inflammatory bowel disease."
Madsen and her colleagues also showed that just two days on the high-sugar diet and the absence of short-chain fatty acids caused an increase in gut permeability, opening interesting avenues of research on how diet may affect the bacteria in our gastrointestinal tract and brain health.
"There is an increasing amount of evidence that suggests there's a link between the bacteria present in our gut and neurodegenerative diseases such as Alzheimer's and Parkinson's," explained Madsen.
"Because our study showed that gut permeability increased quite dramatically in the mice on the high-sugar diet--which means that bacterial products are free to move from the gut, where they normally stay, to the rest of the body--it raises the possibility that this phenomenon might be driving these diseases, but this needs to be looked into."

Frying oil consumption worsened colon cancer and colitis in mice

Foods fried in vegetable oil are popular worldwide, but research about the health effects of this cooking technique has been largely inconclusive and focused on healthy people. For the first time, UMass Amherst food scientists set out to examine the impact of frying oil consumption on inflammatory bowel disease (IBD) and colon cancer, using animal models.
In their paper published Aug. 23 in Cancer Prevention Research, lead author and Ph.D. student Jianan Zhang, associate professor Guodong Zhang, and professor and department head Eric Decker showed that feeding frying oil to mice exaggerated colonic inflammation, enhanced tumor growth and worsened gut leakage, spreading bacteria or toxic bacterial products into the bloodstream.
"People with colonic inflammation or colon cancer should be aware of this research," says Jianan Zhang.
Guodong Zhang, whose food science lab focuses on the discovery of new cellular targets in the treatment of colon cancer and how to reduce the risks of IBD, stresses that "it's not our message that frying oil can cause cancer."
Rather, the new research suggests that eating fried foods may exacerbate and advance conditions of the colon. "In the United States, many people have these diseases, but many of them may still eat fast food and fried food," says Guodong Zhang. "If somebody has IBD or colon cancer and they eat this kind of food, there is a chance it will make the diseases more aggressive."
For their experiments, the researchers used a real-world sample of canola oil, in which falafel had been cooked at 325 F in a standard commercial fryer at an eatery in Amherst, Massachusetts. "Canola oil is used widely in America for frying," Jianan Zhang says.
Decker, an expert in lipid chemistry performed the analysis of the oil, which undergoes an array of chemical reactions during the frying process. He characterized the fatty acid profiles, the level of free fatty acids and the status of oxidation.
A combination of the frying oil and fresh oil was added to the powder diet of one group of mice. The control group was fed the powder diet with only fresh oil mixed in. "We tried to mimic the human being's diet," Guodong Zhang says.
Supported by grants from the U.S. Department of Agriculture, the researchers looked at the effects of the diets on colonic inflammation, colon tumor growth and gut leakage, finding that the frying oil diet worsened all the conditions. "The tumors doubled in size from the control group to the study group," Guodong Zhang says.
To test their hypothesis that the oxidation of polyunsaturated fatty acids, which occurs when the oil is heated, is instrumental in the inflammatory effects, the researchers isolated polar compounds from the frying oil and fed them to the mice. The results were "very similar" to those from the experiment in which the mice were fed frying oil, suggesting that the polar compounds mediated the inflammatory effects.
While more research is needed, the researchers hope a better understanding of the health impacts of frying oil will lead to dietary guidelines and public health policies.
"For individuals with or prone to inflammatory bowel disease," Guodong Zhang says, "it's probably a good idea to eat less fried food."

Ergothioneine has promising effects in preventing neurodegenerative diseases such as dementia and Alzheimer's

Ergothioneine is a natural amino acid with antioxidative properties. It prevents cellular stress, which can lead to brain diseases, neurological damage and cancer. In rats and roundworms, research shows that ergothioneine has promising effects in preventing neurodegenerative diseases such as dementia and Alzheimer's. Also, it has been reported that patients suffering from neurodegenerative diseases have significantly lower blood levels of ergothioneine than others. These findings suggest that ergothioneine might have great potential as a vitamin to prevent or delay the onset of those diseases.
Currently, it is both complicated and expensive to produce ergothioneine with chemical synthesis. However, by engineering and optimising baker's yeast, scientists from The Novo Nordisk Foundation Center for Biosustainability (DTU Biosustain) has for the first time exploited the potential of making ergothioneine in yeast in a bio-based fashion.
In a study published in Frontiers in Bioengineering and Biotechnology Journal, the researchers were able to produce 0.6 gram of ergothioneine pr. liter yeast broth in a small-scale fermentation process.
Too expensive for consumers Because of today's expensive chemical production routes, current market prices of ergothioneine are very high compared to vitamins such as vitamin C and vitamin D that also prevent certain diseases. Thus, one of the main goals for the scientists is to further optimise the production of ergothioneine to reach a higher yield, so it can be sold to the consumer at a much cheaper price in the future.
One of the main reasons for ergothioneine being so expensive at the moment is that the chemical process is costly and the yields fairly low. Furthermore, it has not been tested for its efficacy for the prevention or treatment of neurodegenerative diseases in humans yet. But since the safety assessment of ergothioneine has already been done, it is 'simply' a question of being able to produce enough.
Before the scientists were able to produce ergothioneine in a biobased fashion, some explored the possibility of simply extracting ergothioneine from mushrooms. But again, this would be extremely expensive and require mushroom farms taking up areas of potential farming land.
"By making this important antioxidant in a biobased fashion, you avoid using chemicals or farmland. Yeast is far better at producing ergothioneine than humans or mushrooms could ever be," says the first author Steven van der Hoek.
Enzymes are the key In nature, ergothioneine is produced by bacteria and fungi, but the enzymes bacteria and fungi use for making ergothioneine make up slightly different pathways.
In the study, the scientists chose to screen enzymes from different fungi and from the bacterium Mycobacterium smegmatis in various combinations to identify the clones with the highest ergothioneine production. As production host they used yeast, and they discovered that two specific enzymes NcEgt1 and CpEgt2, both fungal enzymes, made the best combination.
Furthermore, they also investigated potential ergothioneine transporters to increase the yield from their yeast strain. Unfortunately, this did not have any effect.
One thing that worked was to add amino acids that operate as building blocks of ergothioneine to the medium. By doing this, they were able to increase the production of ergothioneine significantly.
Thus, optimisation of the medium was one of the important steps to increase the production to 0.6 g/L in 84 hours, which compares well with the current best-reported production in E. coli that gets 1.3 g/L in 216 hours.
"The bacterial pathway in E. coli uses a lot of energy while the fungal pathway in yeast doesn't. That could lead to a production benefit. Also, yeast is a safe and well-known production host for food supplements" says Steven van der Hoek.
Currently, the scientists are trying to increase productivity by engineering the strain further to make a commercially viable product.
The authors of this study also stress that the positive effects of ergothioneine have so far only been reported in animal models, and, hence, it is too soon to say if this will work in humans. Regardless, ergothioneine production in a larger scale than today could be important to get access to a beneficial dietary supplement.