Antibody Helps Detect Protein Implicated in Alzheimer’s, Other Diseases

May lead to novel ways to diagnose, monitor brain injury

Damaging tangles of the protein tau dot the brains of people with neurodegenerative diseases like Alzheimer’s and boxer’s dementia, and lead to memory loss, confusion and, in some, aggressive behavior. But there is no easy way to determine whether people’s symptoms are linked to tau tangles in their brains. Now, a team led by scientists at Washington University School of Medicine in St. Louis has found a way to measure tau levels in the blood. The method accurately reflects levels of tau in the brain that are of interest to scientists because they correlate with neurological damage. The study, in mice and a small group of people, could be the first step towards a non-invasive test for tau.

Newswise, May 20, 2017 — Damaging tangles of the protein tau dot the brains of people with Alzheimer’s and many other neurodegenerative diseases, including chronic traumatic encephalopathy, which plagues professional boxers and football players.

Such tau-based diseases can lead to memory loss, confusion and, in some, aggressive behavior. But there is no easy way to determine whether people’s symptoms are linked to tau tangles in their brains.

Now, however, a team led by scientists at Washington University School of Medicine in St. Louis has found a way to measure tau levels in the blood. The method accurately reflects levels of tau in the brain that are of interest to scientists because they correlate with neurological damage.

The study, in mice and a small group of people, could be the first step toward a noninvasive test for tau.

While further evaluation in people is necessary, such a test potentially could be used to quickly screen for tau-based diseases, monitor disease progression and measure the effectiveness of treatments designed to target tau.

The research is published April 19 in Science Translational Medicine.

“We showed that you can measure tau in the blood, and it provides insight into the status of tau in the fluid surrounding cells in brain,” said senior author David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology at Washington University School of Medicine in St. Louis.

Tau is a normal brain protein involved in maintaining the structure of neurons. But when tau forms tangles, it damages and kills nearby neurons.

“People with tau diseases have a wide range of symptoms because basically, wherever tau is aggregating, those parts of the brain are degenerating,” Holtzman said. “So if it’s in a memory area, you get memory problems. If it’s in a motor area, you get problems with movement.”

A blood-based screening test, likely years away, would be a relatively easy way to identify people whose symptoms may be due to problems with tau, without subjecting them to potentially invasive, expensive or complicated tests.

“We have no test that accurately reflects the status of tau in the brain that is quick and easy for patients,” Holtzman said. “There are brain scans to measure tau tangles, but they are not approved for use with patients yet.

Tau levels can be measured in the cerebrospinal fluid that surrounds the brain and spinal cord, but in order to get to that fluid, you have to do a spinal tap, which is invasive.”

In the brain, most tau proteins are inside cells, some are in tangles, and the remainder float in the fluid between cells. Such fluid constantly is being washed out of the brain into the blood, and tau comes with it. However, the protein is cleared from the blood almost as soon as it gets there, so the levels, while detectable, typically remain very low.

Holtzman, postdoctoral researcher Kiran Yanamandra, PhD, and MD/PhD student Tirth Patel, along with colleagues from C₂N Diagnostics, AbbVie, the University of California, San Francisco, and Texas Health Presbyterian Hospital, reasoned that if they could keep tau in the blood longer, the protein would accumulate to measurable levels.

 Allowing the protein to accumulate before measuring its levels would magnify – but not distort – differences between individuals, in the same way that enlarging a picture of a grain of sand alongside a grain of rice does not change the relative size of the two, but does make it easier to measure the difference between them.

The researchers injected a known amount of tau protein directly into the veins of mice and monitored how quickly the protein disappeared from the blood. The researchers showed that half the protein normally disappears in less than nine minutes.

When they added an antibody that binds to tau, the half-life of tau was extended to 24 hours. The antibody was developed in the laboratories of Holtzman and Marc Diamond, MD, of the University of Texas Southwestern Medical Center, and is currently licensed to C2N Diagnostics, which is collaborating with the pharmaceutical company AbbVie in developing the technology.

To determine whether the antibody could amplify tau levels in an animal’s blood high enough to be measured easily, they injected the antibody into mice.

Within two days, tau levels in the mice’s blood went up into the easily detectable range. The antibody acted like a magnifying glass, amplifying tau levels so that differences between individuals could be seen more easily.

Tau levels in people’s blood also rose dramatically in the presence of the antibody. The researchers administered the antibody to four people with a tau disease known as progressive supranuclear palsy. Their blood levels of tau rose 50- to 100-fold within 48 hours.

“It’s like a stress test,” Holtzman said. “We appear to be bringing out the ability to see what’s coming from the brain because the antibody amplifies differences by prolonging the time the protein stays in the blood.”

Measuring tau levels in the blood is only useful if it reflects tau levels in the brain, where the protein does its damage, the researchers said.

Both high and low levels of tau in the fluid that surrounds the brain could be a danger sign. Alzheimer’s and chronic traumatic encephalopathy both are associated with high levels of soluble tau, whereas progressive supranuclear palsy and other genetic tau diseases are thought to be associated with low levels.

To see whether elevated brain tau is reflected in the blood, the researchers treated mice with a chemical that injures neurons. The chemical causes tau to be released from the dying neurons, thereby raising tau levels in the fluid surrounding the cells. The scientists saw a corresponding increase of tau in the blood in the presence of the anti-tau antibody.

To lower tau levels, the researchers turned to genetically modified mice that, as they age, have less and less tau floating in their cerebrospinal fluid.

Such mice at 9 months old had significantly lower tau levels in their blood than 3-month-old mice with the same genetic modification, again demonstrating the antibody’s ability to reflect levels of tau in the brain.

“It will be helpful in future studies to see if the measurement of tau in the blood following antibody treatment in humans reflects the state of tau in the brain,” Holtzman said.

Study Unveils New Way to Starve Tumors to Death

Unlike a healthy cell, a sarcoma cell (above) relies on environmental sources of arginine, an important protein building block. Remove environmental arginine and the cell must begin a process called autophagy, or "self-eating," to survive. A second hit to its survival pathways then kills the cell, according to a new study at Washington University School of Medicine in St. Louis. Areas of autophagy are shown in green and the cell nucleus in blue.

Newswise, February 3, 2017 — For decades, scientists have tried to halt cancer by blocking nutrients from reaching tumor cells, in essence starving tumor cells of the fuel needed to grow and proliferate. Such attempts often have disappointed because cancer cells are nimble, relying on numerous backup routes to continue growing.

Now, scientists at Washington University School of Medicine in St. Louis have exploited a common weak point in cancer cell metabolism, forcing tumor cells to reveal the backup fuel supply routes they rely on when this weak point is compromised. Mapping these secondary routes, the researchers also identified drugs that block them. They now are planning a small clinical trial in cancer patients to evaluate this treatment strategy.

The research is published Jan. 24 in Cell Reports.

Studying human cancer cells and mice implanted with patients’ tumor samples, the researchers demonstrate that a double hit — knocking out the weak point and one of the tumor cells’ backup routes — shows promise against many hard-to-treat cancers.

Though present in multiple cancer types, the weak point is particularly common in sarcomas — rare cancers of fat, muscle, bone, cartilage and connective tissues. Doctors treat sarcomas primarily with traditional surgery, radiation and chemotherapy, but such treatments often are not effective.

“We have determined that this metabolic defect is present in 90 percent of sarcomas,” said senior author Brian A. Van Tine, MD, PhD, an associate professor of medicine.

“Healthy cells don’t have this weakness. We have been trying to create a therapy that takes advantage of the metabolic defect because, in theory, it should target only the tumor. Basically, the defect allows us to force the tumor cells to starve.”

To grow and proliferate, tumor cells must have basic building materials. The researchers’ strategy relies on the fact that the vast majority of sarcomas have lost the ability to manufacture their own arginine, a protein building block that cells need to make more of themselves.

Lacking this ability, the cells must harvest arginine from the surrounding environment. The supply of arginine in the blood is abundant, and cancer cells have no trouble scavenging it. But remove this environmental supply of arginine and the cells have a problem.

“When we use a drug to deplete arginine in the blood, the cancer cells panic because they’ve lost their fuel supply,” Van Tine said. “So they rewire themselves to try to survive. In this study, we used that rewiring to identify drugs that block the secondary routes.”

Unlike most cancer therapies, depleting arginine in the blood does not affect healthy cells. Normal cells don’t rely on external sources of arginine because they don’t have the cancer’s metabolic defect.

They continue to make their own arginine, so there is no induced starvation in normal cells even when there is no arginine in the blood. Van Tine said this strategy is based on the properties of a tumor — it shuts down tumor metabolism specifically and nothing else.

Unable to make or obtain external arginine, the tumor cells’ fuel supply routes are forced inward. The cells must begin to metabolize their internal supply of arginine in a process called autophagy, or “self-eating.”

In the case of sarcomas, this state slows or pauses cancer growth but does not kill the cell. During this period, tumor cells appear to be buying time to find yet another internal work-around.

“Cancer doesn’t die when you halt its primary fuel supply,” Van Tine said.

 “Instead, it turns on all these salvage pathways. In this paper, we identified the salvage pathways. Then we showed that when you drug them, too, you kill cells. Our study showed that tumors actually shrink under these conditions. This is the first time tumors have been shown to shrink using just metabolism drugs and no other anti-cancer strategies.”

The arginine-depleting drug is currently in clinical trials investigating its safety and effectiveness against liver, lung, pancreatic, breast and other cancers. But so far, it has been ineffective likely because it has activated the salvage pathways allowing cancer growth to continue. The researchers said the drug may yet become a vital metabolic therapy for cancer as long as it is used in combination with other drugs targeting the backup pathways.

Van Tine and the study’s first author, Jeff C. Kremer, a PhD student in Van Tine’s lab, explained that when cancer cells with this metabolic defect are deprived of environmental arginine, they are forced to shift from a system that burns glucose to a system that burns a different fuel called glutamine.

They showed that adding a glutamine inhibitor to the arginine-depleting drug is lethal to the cells. Eliminating arginine from the blood also rewires serine biology, another backup fuel, so adding serine inhibitors also causes cell death.

This strategy could be applied beyond rare sarcoma tumors because the metabolic defect is often present in other cancers, including certain types of breast, colon, lung, brain and bone tumors, the researchers said.

The new study includes data showing similar anti-tumor responses in cell lines from these cancer types. Van Tine also pointed out that all of the drugs used in the study are either already approved by the U.S. Food and Drug Administration for other conditions or in ongoing clinical trials investigating cancer drugs.

Based on this study and related research, Van Tine and his colleagues at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine are planning a clinical trial of the arginine-depleting drug in patients with sarcomas.

“We will start with a baseline trial testing the arginine-depleting drug against sarcomas with this defect, and then we can begin layering additional drugs on top of that therapy,” Van Tine said.

“Unlike breast cancer, for example, sarcomas currently have no targeted therapies. If this strategy is effective, it could transform the treatment of 90 percent of sarcoma tumors.”

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This work was supported by grants from CJ’s Journey; The Sarcoma Foundation of America; a Sarcoma Alliance for Research and Collaboration Career Development Award; and Polaris Pharmaceuticals. Polaris Pharmaceuticals provided funding and the arginine-depleting drug, ADI-PEG20 (pegylated arginine deiminase).

Kremer JC, Prudner BC, Lange SES, Bean GR, Schultze MB, Brashears CB, Radyk MD, Redlich N, Tzeng S, Kami K, Shelton L, Li A, Morgan Z, Bomalaski JS, Tsukamoto T, McConathy J, Michel LS, Held JM, Van Tine BA. Arginine deprivation inhibits the Warburg effect and upregulates glutamine anaplerosis and serine biosynthesis in ASS1-deficient cancers. Cell Reports. Jan. 24, 2017.

Washington University School of Medicine‘s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Study Details Molecular Roots of Alzheimer’s

Credit: Daniel L. Kober

A new study at Washington University School of Medicine in St. Louis details the structure of TREM2, a protein involved in Alzheimer's disease and other neurodegenerative disorders

Cellular 'housekeeping' molecule’s structure linked to neurodegeneration

Newswise, January 3, 2017 — Scientists at Washington University School of Medicine in St. Louis have detailed the structure of a molecule that has been implicated in Alzheimer’s disease.

Knowing the shape of the molecule — and how that shape may be disrupted by certain genetic mutations — can help in understanding how Alzheimer’s and other neurodegenerative diseases develop and how to prevent and treat them.

The idea that the molecule TREM2 is involved in cognitive decline — the hallmark of neurodegenerative diseases, including Alzheimer’s — has gained considerable support in recent years.

Past studies have demonstrated that certain mutations that alter the structure of TREM2 are associated with an increased risk of developing late-onset Alzheimer’s, frontal temporal dementia, Parkinson’s disease and sporadic amyotrophic lateral sclerosis (ALS).

Other TREM2 mutations are linked to Nasu-Hakola disease, a rare inherited condition that causes progressive dementia and death in most patients by age 50.

“We don’t know exactly what dysfunctional TREM2 does to contribute to neurodegeneration, but we know inflammation is the common thread in all these conditions,” said senior author Thomas J. Brett, PhD, an assistant professor of medicine.

“Our study looked at these mutations in TREM2 and asked what they do to the structure of the protein itself, and how that might impact its function. If we can understand that, we can begin to look for ways to correct it.”

The analysis of TREM2 structure, completed by first author, Daniel L. Kober, a doctoral student in Brett’s lab, revealed that the mutations associated with Alzheimer’s alter the surface of the protein, while those linked to Nasu-Hakola influence the “guts” of the protein. The difference in location could explain the severity of Nasu-Hakula, in which signs of dementia begin in young adulthood.

The internal mutations totally disrupt the structure of TREM2, resulting in fewer TREM2 molecules. The surface mutations, in contrast, leave TREM2 intact but likely make it harder for the molecule to connect to proteins or send signals as normal TREM2 molecules would.

TREM2 lies on the surface of immune cells called microglia, which are thought to be important “housekeeping” cells. Via a process called phagocytosis, such cells are responsible for engulfing and cleaning up cellular waste, including the amyloid beta that is known to accumulate in Alzheimer’s disease.

 If the microglia lack TREM2, or the TREM2 that is present doesn’t function properly, the cellular housekeepers can’t perform their cleanup tasks.

“Exactly what TREM2 does is still an open question,” Brett said. “We know mice without TREM2 have defects in microglia, which are important in maintaining healthy brain biology. Now that we have these structures, we can study how TREM2 works, or doesn’t work, in these neurodegenerative diseases.”

TREM2 also has been implicated in other inflammatory conditions, including chronic obstructive pulmonary disease and stroke, making the structure of TREM2 important for understanding chronic and degenerative diseases throughout the body, he added.

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This work was supported by the National Institutes of Health (NIH), grant numbers R01-HL119813, R01-AG044546, R01-AG051485, R01-HL120153, R01-HL121791, K01-AG046374, T32-GM007067, K08-HL121168, and P50-AG005681-30.1; the Burroughs-Wellcome Fund; the Alzheimer’s Association, grant number AARG-16-441560; and the American Heart Association, grant number PRE22110004. Results were derived from work performed at Argonne National Laboratory (ANL) Structural Biology Center. ANL is operated by U. Chicago Argonne, LLC, for the U.S. DOE, Office of Biological and Environmental Research, supported by grant number DE-AC02-06CH11357.

Kober DL, Alexander-Brett JM, Karch CM, Cruchaga C, Colonna M, Holtzman MJ, Brett TJ. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. eLife. Dec. 20, 2016.

Washington University School of Medicine‘s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Cause Of Inflammation In Diabetes Identified

Could be target for preventing related heart attacks, strokes

Too much fat in the diet promotes insulin resistance by spurring chronic inflammation. Researchers at Washington University School of Medicine have developed a way to block production of fatty acids in these immune cells in mice and protect them from diet-induced diabetes.

Newswise, November 7, 2016 — Inflammation is one of the main reasons why people with diabetes experience heart attacks, strokes, kidney problems and other, related complications.

Now, in a surprise finding, researchers at Washington University School of Medicine in St. Louis have identified a possible trigger of chronic inflammation.

Too much fat in the diet promotes insulin resistance by spurring chronic inflammation. But the researchers discovered, in mice, that when certain immune cells can’t manufacture fat, the mice don’t develop diabetes and inflammation, even when consuming a high-fat diet.

The study is available Nov. 2 as an advance online publication from the journal Nature.

“The number of people with diabetes has quadrupled worldwide over the last 20 years,” said senior investigator Clay F. Semenkovich, the Irene E. and Michael M. Karl Professor and director of the Division of Endocrinology, Metabolism & Lipid Research at the School of Medicine.

“We have made modest progress in making it less likely for some people with diabetes to have heart attacks and strokes.

“However, those receiving optimal therapy are still much more likely to die from complications driven by chronic inflammation that is, at least in part, generated by these immune cells.

“But by blocking the production of fat inside these cells, it may be possible to prevent inflammation in people with diabetes and even in other conditions, such as arthritis and cancer, in which chronic inflammation plays a role. This could have a profound impact on health.”

Semenkovich’s team made genetically altered mice that could not make the enzyme for fatty acid synthase (FAS) in immune cells called macrophages. Without the enzyme, it was impossible for the mice to synthesize fatty acids, a normal part of cell metabolism.

“We were surprised to find that the mice were protected from diet-induced diabetes,” said first author Xiaochao Wei, PhD, an instructor of medicine. “They did not develop the insulin resistance and diabetes that normally would have been induced by a high-fat diet.”

Through a series of experiments in the animals and in cell cultures, the researchers, including Douglas F. Covey, PhD, a professor of developmental biology and biochemistry, and Daniel S. Ory, MD, a professor of medicine and of cell biology and physiology, found that if macrophages could not synthesize fat from within, the external membranes of those cells could not respond to fat from outside the cells. That prevented the cells from contributing to inflammation.

But eliminating inflammation altogether is not the answer to preventing diabetic complications because inflammation is also vital for clearing infectious pathogens from the body and helps wounds heal. Still, Semenkovich said the new findings may have profound clinical implications.

“An inhibitor of fatty acid synthase actually is now in clinical trials as a potential cancer treatment,” he explained.

“And other drugs have been developed to inhibit fatty acid synthase in diabetes, too. One possibility that our work suggests is that altering the lipid content in the cell membrane may help block cancer metastases and complications of diabetes.”

Drugs currently in use to block fatty acid synthase, as well as other developing strategies, potentially could allow for chronic inflammation to be blocked, without completely eliminating the ability of macrophages to fight infection.

The researchers also plan to take a look at existing drug compounds that change the lipid composition in cells. Such medications failed in clinical trials, but they may have an effect on the membranes of macrophages and therefore may lower the risk of diabetes complications, Semenkovich said.

Wei X, Song H, Rizzo MG, Sidhu R, Covey DF, Ory DS, Semenkovich CF. Fatty acid synthesis configures the plasma membrane for inflammation in diabetes. Nature. Nov. 2, 2016. http://www.dx.doi.org/10.1038/nature20117

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases; the National Heart, Lung, and Blood Institute; and the National Center for Research Resources of the National Institutes of Health (NIH), grant numbers DK101392, DK076729, DK088083, DK20579, DK56341, RR00954 and HL067773. Additional funds came from the Taylor Family Institute for Innovative Psychiatric Research.

Washington University School of Medicine‘s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals.

The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Earlier Alzheimer’s Diagnosis May Be Possible With New Imaging Compound

New tool detects Alzheimer’s protein, may help identify brain changes, assess treatment effects

Credit: Ping Yan and Jin-Moo Lee

Researchers at Washington University School of Medicine in St. Louis have developed a chemical compound that detects the Alzheimer’s protein amyloid beta better than current FDA-approved agents. The compound potentially may be used in brain scans to identify people in the earliest stages of Alzheimer’s disease.  In the image, the compound has passed from the bloodstream of a living mouse into its brain, where it is detected by a positron emission tomography (PET) scan. Arrows indicate clumps of amyloid beta.

Newswise, November 7, 2016 — By the time unambiguous signs of memory loss and cognitive decline appear in people with Alzheimer’s disease, their brains already are significantly damaged, dotted with clumps of a destructive protein known as amyloid beta. For years, scientists have sought methods and clues to help identify brain changes associated with Alzheimer’s earlier in the disease process, so they can try to stop or even reverse the changes before they severely affect people’s lives.

Now, researchers at Washington University School of Medicine in St. Louis have developed a chemical compound, named Fluselenamyl, that detects amyloid clumps better than current FDA-approved compounds.

If a radioactive atom is incorporated into the compound, its location in a living brain can be monitored using positron emission tomography (PET) scans.

The compound, described in a paper published Nov. 2 in Scientific Reports, one of the Nature journals, potentially could be used in brain scans to identify the signs of early-stage Alzheimer’s disease or to monitor response to treatment.

“Fluselenamyl is both more sensitive and likely more specific than current agents,” said Vijay Sharma, PhD, a professor of radiology, of neurology and of biomedical engineering, and the study’s senior author.

“Using this compound, I think we can reduce false negatives, potentially do a better job of identifying people in the earliest stages of Alzheimer’s disease and assess the effects of treatments.”

Amyloid plaques are one of the most telltale findings in the brains of people with Alzheimer’s disease. The neurons near such plaques are often dead or damaged, and this loss of brain cells is thought to account for difficulty with thinking, memory loss and confusion experienced by Alzheimer’s patients.

Amyloid plaques can be either diffuse or compact. The compact kind has long been associated with the disease, but conventional wisdom has held that diffuse plaques are benign, since they can be found in the brains of elderly people without any symptoms of Alzheimer’s disease, as well as the brains of those with Alzheimer’s. Sharma believes that diffuse plaques may mark the earliest stages of the disease.

“It is a relatively underexplored area in the development of Alzheimer’s pathology,” Sharma said.

“Since current approved agents don’t detect diffuse plaques, there is no reliable noninvasive imaging tool to investigate this aspect in animal models or in patients. Our compound could be used to study the role of diffuse plaques.”

Using human amyloid beta proteins, Sharma and colleagues showed that Fluselenamyl bound to such proteins two to 10 times better than each of the three FDA-approved imaging agents for detecting amyloid beta.

In other words, Fluselenamyl detected much smaller clumps of the protein, indicating that it may be able to detect the brain changes associated with Alzheimer’s disease earlier.

To determine whether Fluselenamyl can detect plaques in the brain, the researchers used the compound to stain brain slices from people who had died of Alzheimer’s disease and, as controls, people of similar ages who had died of other causes.

The brain slices from the Alzheimer’s patients, but not the controls, were identified as containing plaques.

When a radioactive atom was incorporated into the compound, the researchers found very little interaction between Fluselenamyl and the healthy white matter in the human brain slices.

“A huge obstacle with existing state-of-the-art PET agents approved for plaque detection is that they tend to bind indiscriminately to the brain’s white matter, which creates false positives on the scans,” Sharma said.

Nonspecific binding to other parts of the brain creates “noise,” which makes it difficult to distinguish samples with plaques from those without.

A similar experiment comparing mice genetically predisposed to develop amyloid plaques with normal control mice showed the same pattern of high sensitivity for amyloid beta and low binding to healthy white matter.

Furthermore, Sharma and colleagues showed that when Fluselenamyl with the radioactive atom is injected intravenously into mice, the compound can cross the blood-brain barrier, bind to any plaques in their brains and be detected by PET scan.

In mice without plaques, the compound is quickly flushed from the brain and then excreted from the body.

The next step is to move to testing in patients. Sharma already has submitted an application to the National Institutes of Health (NIH) for a phase 0 trial, to establish whether Fluselenamyl is safe for use in humans and behaves in the human body the same way it behaves in mice.

Phase 0 trials involve a low dose given to a small number of people to learn how a molecule is processed in the body and how it affects the body.

“Ideally, we’d like to look at patients with very mild symptoms who are negative for Alzheimer’s by PET scan to see if we can identify them using Fluselenamyl,” Sharma said.

 “One day, we may be able to use Fluselenamyl as part of a screening test to identify segments of the population that are going to be at risk for development of Alzheimer’s disease. That’s the long-term goal.”

Natural Compound Reduces Signs Of Aging In Healthy Mice

Safety of NMN being tested in small clinical trial in Japan

Newswise, October 31, 2016 — Much of human health hinges on how well the body manufactures and uses energy. For reasons that remain unclear, cells’ ability to produce energy declines with age, prompting scientists to suspect that the steady loss of efficiency in the body’s energy supply chain is a key driver of the aging process.

Now, scientists at Washington University School of Medicine in St. Louis have shown that supplementing healthy mice with a natural compound called NMN can compensate for this loss of energy production, reducing typical signs of aging such as gradual weight gain, loss of insulin sensitivity and declines in physical activity.

The study is published Oct. 27 in the journal Cell Metabolism

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“We have shown a way to slow the physiologic decline that we see in aging mice,” said Shin-ichiro Imai, MD, PhD, a professor of developmental biology and of medicine.

“This means older mice have metabolism and energy levels resembling that of younger mice. Since human cells rely on this same energy production process, we are hopeful this will translate into a method to help people remain healthier as they age.”

Imai is working with researchers conducting a clinical trial to test the safety of NMN in healthy people. The phase 1 trial began earlier this year at Keio University School of Medicine in Tokyo.

With age, the body loses its capacity to make a key element of energy production called NAD (nicotinamide adenine dinucleotide). Past work by Imai and co-senior author Jun Yoshino, MD, PhD, an assistant professor of medicine, has shown that NAD levels decrease in multiple tissues as mice age.

Past research also has shown that NAD is not effective when given directly to mice so the researchers sought an indirect method to boost its levels. To do so, they only had to look one step earlier in the NAD supply chain to a compound called NMN (nicotinamide mononucleotide).

NMN can be given safely to mice and is found naturally in a number of foods, including broccoli, cabbage, cucumber, edamame and avocado.

The new study shows that when NMN is dissolved in drinking water and given to mice, it appears in the bloodstream in less than three minutes. Importantly, the researchers also found that NMN in the blood is quickly converted to NAD in multiple tissues.

“We wanted to make sure that when we give NMN through drinking water, it actually goes into the blood circulation and into tissues,” Imai said. “Our data show that NMN absorption happens very rapidly.”

To determine the long-term effects of giving NMN, Imai, Yoshino and their colleagues studied three groups of healthy male mice fed regular mouse chow diets.

Starting at five months of age, one group received a high dose of NMN-supplemented drinking water, another group received a low dose of the NMN drinking water, and a third group served as a control, receiving no NMN.

The researchers compared multiple aspects of physiology between the groups, first at 5 months of age and then every three months, until the mice reached 17 months of age. Typical laboratory mice live about two years.

The researchers found a variety of beneficial effects of NMN supplementation, including in skeletal muscle, liver function, bone density, eye function, insulin sensitivity, immune function, body weight and physical activity levels. But these benefits were seen exclusively in older mice.

“When we give NMN to the young mice, they do not become healthier young mice,” Yoshino said.

“NMN supplementation has no effect in the young mice because they are still making plenty of their own NMN. We suspect that the increase in inflammation that happens with aging reduces the body’s ability to make NMN and, by extension, NAD.”

In skeletal muscle, the investigators — including the study’s first author, Kathryn Mills, the research supervisor in Imai’s lab — found that NMN administration helps energy metabolism by improving the function of mitochondria, which operate as cellular power plants.

They also found that mice given NMN gained less weight with aging even as they consumed more food, likely because their boosted metabolism generated more energy for physical activity.

The researchers also found better function of the mouse retina with NMN supplementation, as well as increased tear production, which is often lost with aging. They also found improved insulin sensitivity in the older mice receiving NMN, and this difference remained significant even when they corrected for differences in body weight.

In a paper published earlier this year in Cell Reports, Yoshino and his colleagues revealed more details of how NAD works in influencing glucose metabolism and the body’s fat tissue.

In that study, the mice had a defect in the ability to manufacture NAD only in the body’s fat tissue. The rest of their tissues and organs were normal.

“Even though NAD synthesis was stopped only in the fat tissue, we saw metabolic dysfunction throughout the body, including the skeletal muscle, the heart muscle, the liver and in measures of the blood lipids,” Yoshino said.

“When we gave NMN to these mice, these dysfunctions were reversed. That means NAD in adipose tissue is a critical regulator of whole body metabolism.”

Added Imai, “This is important because Jun showed that if you mess up NAD synthesis only in fat tissue, you see insulin resistance everywhere. Adipose tissue must be doing something remarkable to control whole body insulin sensitivity.”

During the long-term NMN study in healthy mice, Imai also said they monitored the animals for any potential increase in cancer development as a result of NMN administration.

“Some tumor cells are known to have a higher capability to synthesize NAD, so we were concerned that giving NMN might increase cancer incidence,” Imai said. “But we have not seen any differences in cancer rates between the groups.”

The phase 1 trial in Japan is using NMN manufactured by Oriental Yeast Co., which also provided the NMN used in these mouse studies. Outside of this clinical trial, high-grade NMN for human consumption is not commercially available. But there’s always broccoli.

Free e-Book Offers Tips for Reducing Breast Cancer Risk at Nearly Any Age​​​​​​​​​​​​​

Newswise, September 4, 2015 — Surprisingly, preventing breast cancer can begin as early as age 2. Eating right, being physically active and keeping weight in check – even at a young age – can substantially lower breast cancer risk.

But even if healthy behaviors don’t begin until age 50, women can still reduce their risk of breast cancer by up to half.

A free e-book by researchers at Washington University School of Medicine in St. Louis provides practical, science-based advice for lowering breast cancer risk at every stage of life. Available for the iPad and iPhone, “Together — Every Woman’s Guide to Preventing Breast Cancer” is written for a lay audience to help women improve their breast health and the breast health of their loved ones.

“Breast cancer is the No. 1 health fear for many women,” said Graham Colditz, MD, DrPH, the Niess-Gain Professor of Surgery at the School of Medicine. “With this e-book, we hope to put breast cancer risk in perspective and provide simple, everyday prevention tips that apply from childhood through midlife and beyond.”

The e-book is based on decades of research reviewed by Colditz, who also is associate director of Siteman Cancer Center at Barnes-Jewish Hospital​ and Washington University School of Medicine. His co-authors are Katherine Weilbaecher, MD, a breast cancer oncologist and professor of medicine at the School of Medicine, and medical writer Hank Dart.

In addition to age-specific breast cancer prevention tips for women, the e-book includes advice for parents who want to steer their daughters toward healthy behaviors.

“We’re finding more and more that youth and young adulthood are key periods in determining breast cancer risk later in life, so we’ve created down-to-earth guides for parents and grandparents to help young girls in their lives develop lifelong healthy habits,” Colditz said.

Prevention tips targeted to children and adolescents focus largely on helping them maintain healthy growth, eat healthy food and get enough activity every day. When children are old enough, discussions of the dangers of tobacco and alcohol are included.

For adults, the e-book focuses on nine key steps for preventing breast cancer:

​* Keep weight in check;
* Be physically active;
​* Avoid too much alcohol;
​* Don’t smoke;
​* Breastfeed, if possible;
​* Avoid birth control pills, particularly after age 35 or if a smoker;
​* Avoid hormone replacement therapy after menopause;
​* Find out one’s family history; and
​* If high-risk, consider risk-reducing medications.

About 12 of every 100 women born in the U.S. will be diagnosed with breast cancer at some point in their lives, Weilbaecher said. A healthy lifestyle started during childhood and continued through adulthood could prevent breast cancer in more than seven of these women.

However, even if women don’t practice healthy behaviors until midlife, they still can reduce their risk of breast cancer by up to 50 percent. And most of the same cancer-fighting activities also boost heart health and lower the risk of diabetes, stroke, colon cancer, osteoporosis and other conditions.

“Teaching our daughters and granddaughters how to live healthy lives is a gift that lasts a lifetime,” Weilbaecher said. 

“It’s almost never too early in life to lay the foundation for healthy behaviors. And it’s almost never too late to start.”​​​​​​​​​​​​​​​

Colditz and Dart also developed Zuum – a free iPad app that estimates a person’s risk of disease and provides tailor-made tips to boost overall health – and Your Disease Risk​, the website it’s based upon.

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Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’shospitals. 

The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Siteman Cancer Center, the only National Cancer Institute-designated Comprehensive Cancer Center in Missouri, is ranked among the top cancer facilities in the nation by U.S. News & World Report. Comprising the cancer research, prevention and treatment programs of Barnes-Jewish Hospital and Washington University School of Medicine, Siteman is also Missouri’s only member of the National Comprehensive Cancer Network.