Researchers make tiny, aged brains to study Alzheimer’s

Researchers led by City of Hope, a world-renowned research and treatment center for cancer, diabetes and other life-threatening diseases, have developed a powerful miniature brain platform to study the mechanistic causes of Alzheimer’s disease and to test dementia drugs in development, reports a new study published today in Advanced Science.

“Drug development for Alzheimer’s disease has run into challenges due to incomplete understanding of the disease’s pathological mechanisms,” said Yanhong Shi, Ph.D., the Herbert Horvitz Professor in Neuroscience and director of the Division of Stem Cell Biology Research within the Department of Developmental and Stem Cell Biology at Beckman Research Institute of City of Hope.

“Preclinical research in this arena predominantly uses animal models, but there is a huge difference between humans and animals such as rodents, especially when it comes to brain architecture. We, at City of Hope, have created a miniature brain model that uses human stem cell technology to study Alzheimer’s disease and, hopefully, to help find treatments for this devastating illness.”

City of Hope researchers were able to model sporadic Alzheimer’s disease, the most common form of the condition, using “brain organoids” derived using human induced pluripotent stem cell (hiPSC) technology. Because Alzheimer’s is a disease of age, the scientists exposed the models to serum to mimic age-associated blood-brain barrier breakdown. Then they ran the organoids through different experiments to test known Alzheimer’s biomarkers, including elevated levels of amyloid plaques and tau tangles as well as synaptic breaks linked to cognitive decline, among other pathological phenotypes brought on by the condition.

More than 6 million people are living with Alzheimer’s disease, which kills more people than breast and prostate cancer combined, reports the Alzheimer’s Association. The heartbreaking degenerative disease affects not only the individual diagnosed with the condition, but also their primary caregiver, family and friends. No cure currently exists, and available treatments merely address symptoms rather than the root cause.

“Other studies using brain organoids to examine Alzheimer’s disease used miniature brain models that are phenotypically young, but to truly understand what happens when Alzheimer’s strikes, we need to use age-associated models, and that’s what we did in this research project when we exposed the miniature brains to serum,” said Xianwei Chen, Ph.D., first author of the study and postdoctoral fellow at City of Hope. “We believe the age-associated brain organoids we generated will provide a powerful platform for us to find effective treatments for disorders affecting the human body’s most complex organ.”

Preclinical research using brain organoids found that exposure to serum from blood could induce multiple Alzheimer’s symptoms, suggesting combination therapies targeting multiple pathological alterations likely would be more effective than single-target therapies currently in development. The researchers studied late-onset or sporadic Alzheimer’s disease, which accounts for most cases (95% sporadic vs. 5% inherited). They found that attempting a single therapy — for example inhibiting only amyloid or tau proteins — did not reduce the levels of tau or amyloid, respectively, suggesting that these two key biomarkers likely cause disease progression independently. Moreover, exposure to serum from blood — which mimics a leaky blood-brain barrier — could cause breaks in synaptic connections that help brains remember things and function properly.

Matt Huentelman, Ph.D., professor of neurogenomics at the Translational Genomics Research Institute (TGen), said the brain model developed by City of Hope provides a new avenue for examining emerging treatments for this memory-robbing disease. Huentelman is a leading expert in the genetic study of Alzheimer’s disease and was not part of this study.

“Using the model developed in this City of Hope-led study could help accelerate the evaluation of potential treatment options, giving a new sense of hope to Alzheimer’s patients and their families,” he said.

The study, “Modeling sporadic Alzheimer’s disease in human brain organoids under serum exposure,” was done in collaboration with University of California Irvine, Banner Sun Health Research Institute, Banner Alzheimer’s Institute and Washington University in St. Louis. It was supported by the Louise and Herbert Horvitz Charitable Foundation, the Sidell-Kagan Foundation, the Christopher Family Endowed Innovation Fund, the National Institute on Aging of the National Institutes of Health (R01 AG056305, RF1 AG061794, R56 AG061171, P30 AG019610, RF1 DA048813, R01 AG056303, P30 AG066519) and the National Cancer Institute of the National Institutes of Health (P30CA33572).

CONTACT
Zen Vuong
626-409-9367
zvuong@coh.org

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Scientists explore the latent regenerative potential of the inner ear

Scientists from the USC Stem Cell laboratory of Neil Segil have identified a natural barrier to the regeneration of the inner ear’s sensory cells, which are lost in hearing and balance disorders. Overcoming this barrier may be a first step in returning inner ear cells to a newborn-like state that’s primed for regeneration, as described in a new study published in Developmental Cell.

“Permanent hearing loss affects more than 60 percent of the population that reaches retirement age,” said Segil, who is a Professor in the Department of Stem Cell Biology and Regenerative Medicine, and the USC Tina and Rick Caruso Department of Otolaryngology – Head and Neck Surgery. “Our study suggests new gene engineering approaches that could be used to channel some of the same regenerative capability present in embryonic inner ear cells.”

In the inner ear, the hearing organ, which is the cochlea, contains two major types of sensory cells: “hair cells” that have hair-like cellular projections that receive sound vibrations; and so-called “supporting cells” that play important structural and functional roles.

When the delicate hair cells incur damage from loud noises, certain prescription drugs, or other harmful agents, the resulting hearing loss is permanent in older mammals. However, for the first few days of life, lab mice retain an ability for supporting cells to transform into hair cells through a process known as “transdifferentiation”, allowing recovery from hearing loss. By one week of age, mice lose this regenerative capacity—also lost in humans, probably before birth.

Based on these observations, postdoctoral scholar Litao Tao, PhD, graduate student Haoze (Vincent) Yu, and their colleagues took a closer look at neonatal changes that cause supporting cells to lose their potential for transdifferentiation.

In supporting cells, the hundreds of genes that instruct transdifferentiation into hair cells are normally turned off. To turn genes on and off, the body relies on activating and repressive molecules that decorate the proteins known as histones.  In response to these decorations known as “epigenetic modifications,” the histone proteins wrap the DNA into each cell nucleus, controlling which genes are turned “on” by being loosely wrapped and accessible, and which are turned “off” by being tightly wrapped and inaccessible. In this way, epigenetic modifications regulate gene activity and control the emergent properties of the genome.

In the supporting cells of the newborn mouse cochlea, the scientists found that hair cell genes were suppressed by both the lack of an activating molecule, H3K27ac, and the presence of the repressive molecule, H3K27me3.  However, at the same time, in the newborn mouse supporting cells, the hair cell genes were kept “primed” to activate by the presence of yet a different histone decoration, H3K4me1.  During transdifferentiation of a supporting cell to a hair cell, the presence of H3K4me1 is crucial to activate the correct genes for hair cell development.

Unfortunately with age, the supporting cells of the cochlea gradually lost H3K4me1, causing them to exit the primed state. However, if the scientists added a drug to prevent the loss of H3K4me1, the supporting cells remained temporarily primed for transdifferentiation. Likewise, supporting cells from the vestibular system, which naturally maintained H3K4me1, were still primed for transdifferentiation into adulthood.

“Our study raises the possibility of using therapeutic drugs, gene editing, or other strategies to make epigenetic modifications that tap into the latent regenerative capacity of inner ear cells as a way to restore hearing,” said Segil. “Similar epigenetic modifications may also prove useful in other non-regenerating tissues, such as the retina, kidney, lung, and heart.”

Additional co-authors of the study include Juan Llamas, Talon Trecek, Xizi Wang, and Zlatka Stojanova in the Segil Lab at USC, and Andrew K. Groves at Baylor College of Medicine.

Sixty percent of this project was supported by federal funding from the National Institute on Deafness and Other Communication Disorders (R01DC015829, R01DC014832, T32DC009975, F31DC017376). Additional funding came from the Hearing Restoration Project at Hearing Health Foundation.

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Stinkweed could make a cleaner bio-jet fuel

A common farm weed could make a “greener” jet fuel with fewer production-related environmental impacts than other biofuels, a new study indicates.

Growing the weed, pennycress – often called stinkweed – as a crop requires less fertilizer and fewer pesticides than other plants that can be used to make renewable jet fuel, according to the study. Pennycress also requires fewer farm operations, such as soil tilling, than other potential biofuel crops, reducing the associated environmental costs. Those costs include carbon dioxide emissions that cause the climate to change, as well as other emissions that pollute the air.

Environmental impacts could be further mitigated through farm management techniques that keep fertilizer on fields, rather than allowing it to run off into nearby watersheds, the study suggests. Such techniques can add to the financial cost of growing crops, but reduce their environmental footprints.

“Reducing greenhouse gas emissions from air travel will mean not just incremental changes, but a fundamental change in how we have been producing fuel and where that fuel comes from,” said Ajay Shah, senior author of the study and associate professor of food, agricultural and biological engineering at The Ohio State University in Wooster. “And what we found is that pennycress might make a very good alternative fuel, especially when you consider the environmental costs of producing it.”

The study was published recently online in the journal Applied Energy.

For this study, the researchers estimated the environmental impacts of growing pennycress, transporting it to a biorefinery and converting it to a usable jet fuel. They also accounted for the environmental costs of burning leftover byproducts of refining the pennycress seed into fuel.

Those environmental costs include fertilizer and pesticide use, water consumption and the energy required to harvest and transport pennycress seeds from a farm to a biorefinery and process them into usable fuel.

The researchers built computer models to determine how much total energy it would take to produce jet fuel from pennycress seeds and compared those estimates with the energy needed for producing biofuels from other crops. The data for the models came from existing studies about biofuel production.

Their models showed that it took about half as much energy to produce jet fuel from pennycress as it did to produce jet fuel from canola or sunflowers, two other potential bio-jet fuel crops. Pennycress oil production used about a third as much energy as soybean oil production, the researchers found, and the energy needed for turning pennycress into jet fuel was about the same as that used to produce fuel from the flowering plant camelina, another biofuel crop.

Renewable jetfuels are not yet financially competitive with fossil fuel-based fuels, Shah said. But calculating the environmental impacts of alternative bio-based fuels should help both farmers and policymakers as they try to limit carbon dioxide in the Earth’s atmosphere and, hopefully, to slow or stop climate change.

“Pennycress also makes an appealing alternative jet fuel because of its growing season,” Shah said. “It is a winter cover crop that can be grown between corn season and soybean season, giving the same body of farmland an extra production cycle each year.

“Pennycress can be planted when corn is still standing in the field, before the corn harvest,” he said. “And it can be harvested before the soybean crops are planted. The bottom line is it can be used as a cover crop, it doesn’t divert any agricultural production land, and it has suitable properties for renewable jet fuel production.”

Greenhouse gas emissions from air travel contribute to climate change, accounting for about 2% of all human-induced carbon-dioxide emissions, according to various groups that study the effects of transportation on climate change.

“Reducing those emissions will almost certainly mean finding cleaner alternatives to jet fuels made from fossil fuels,” Shah said. “Studies like this one can help determine the best alternative.

“When it comes to pennycress, production and logistics are the big contributors to both the environmental impacts and the costs, and those are the challenge areas ­– they have to be streamlined and solved to make it more efficient,” he said. “If we could improve those areas, we could make production more energy-efficient and substantially lower the costs and environmental impacts.”

This work was supported by funding from the U.S. Department of Energy.

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Artificial Intelligence May Find Signs Of Alzheimer’s In Neuroimaging Data

Shuiwang Ji, associate professor in the Department of Computer Science and Engineering at Texas A&M University, is one of the principal investigators on a $6 million grant from the National Institutes of Health to develop artificial intelligence-driven methods to automate the process of finding subtle telltale signs of Alzheimer’s disease in neuroimaging data. Ji’s team shares $1.2 million of the grant.

Ji will lead the research team tasked with developing advanced deep-learning methods for finding relevant neural signatures lurking within neuroimages taken using different techniques, such as PET scans and MRIs.

“I feel very excited with this collaborative opportunity to make scientific discoveries in medical domains using deep learning and artificial intelligence,” said Ji, who has extensive expertise in machine learning, deep learning and medical image analysis.

Alzheimer’s disease affects 5.6 million Americans over the age of 65, and its symptoms are most noticeably the progressive impairment of cognitive and memory functions. It is also currently the most common form of dementia in the elderly. Despite copious amounts of studies on Alzheimer’s over the years, researchers’ understanding of the biology and progression of the disease remains limited, so there are limited advances in therapeutics and preventive strategies.

Ji said the research team expects to discover new genetic biomarkers relevant to Alzheimer’s, which may lead to understanding the molecular basis of the disease, and in turn, uncover a potential new treatment.

Researchers will leverage existing neuroimaging and genetic data resources from the UK Biobank, the Alzheimer’s Disease Sequencing Project, the Alzheimer’s Disease Neuroimaging Initiative, and the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.

Other collaborators on this research areDegui Zhi, associate professor with the UTHealth School of Biomedical Informatics, and Myriam Fornage, professor at the Center for Human Genetics at UTHealth.

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Bee careful: Insecticide is harmful in any amount

A new UC Riverside study shows that a type of insecticide made for commercial plant nurseries is harmful to a typical bee even when applied well below the label rate.

The study was published today in the journal Proceedings of the Royal Society B: Biological Sciences.

Chemically similar to nicotine, neonicotinoids are insecticides that protect against plant-consuming insects like aphids, but seriously harm beneficial insects, like bees. They are widely used by commercial growers.

Much research has focused on their use in food crops like canola, in which they are typically applied at low doses. However, this study is one of the few to examine neonicotinoid application in potted ornamental plants, which can represent more potent, acute sources of exposure to the toxin for bees.

“Neonicotinoids are often used on food crops as a seed treatment,” explained UCR entomologist and lead study author Jacob Cecala. “But they’re usually applied in higher amounts to ornamental plants for aesthetic reasons. The effects are deadly no matter how much the plants are watered.”

Cecala said he was surprised by this result, given that neonicotinoids are water soluble. Going into the study, he assumed that more water would dilute the amount of harm they caused the bees. The researchers were also curious whether increased watering could benefit bees despite insecticide exposure by increasing the quantity or quality of nectar offered by the plants.

To test these assumptions, the researchers raised bees on flowering native plants in pots that either received a lot of watering, or a little. Plants were selected based on their popularity at nurseries, drought tolerance to ensure blooming even without much water, and their attractiveness to bees. In addition, half the plants were treated with the insecticide.

Though increased water decreased the pesticide’s potency in the nectar of the flowers, the negative effects on bees were still observed.

“Unfortunately, we observed a 90% decrease in the bees’ reproduction with both high and low levels of irrigation,” Cecala said.

This study is also one of the few to examine neonicotinoid effects via ornamental plants on solitary bees, which make up more than 90% of native bee species in North America, and an even higher percentage in California.

Solitary bees are not bees who have left the hive and are now alone. This is a type of bee that lives alone, does not produce honey, and does not have a queen or live in a hive. Because they do not have a store of honey to protect, they are also not aggressive.

“Solitary bees are more representative of the ecosystem here, and they are potentially more vulnerable to pesticides,” said UCR entomologist and study co-author Erin Rankin.

If a worker bee that is social — like the honeybee — gets exposed to insecticide and dies, it won’t necessarily affect the longevity of the hive. However, if a solitary bee dies, its lineage is cut short.

In this study, the researchers used alfalfa leafcutter bees, which make their nests in tunnels and lay eggs one at a time. They are very similar to California’s solitary native bees and are part of a genus that can be found worldwide.

The first time Cecala and Rankin tried this experiment, they used the concentration of insecticide recommended on the product label. All the bees died in a matter of days.

The next time they ran the experiment, they used a third of the recommended dose and still found negative effects on reproduction, the ability of the bees to feed themselves, and overall fitness. “It almost completely wiped them out,” Cecala said.

Though this study used a neonicotinoid product formulated for nurseries, formulations of similar products for home gardeners also tend to be highly concentrated.

Plants in nurseries or residential backyards represent a smaller total area than food plant fields like corn or soy. However, high-potency neonicotinoid products can have a big effect even in small areas. In 2013, neonicotinoids applied to flowering trees in a retail parking lot in Oregon caused a massive bumblebee die off, with more than 25,000 found dead.

The researchers recommend that nurseries quantify the amount of pesticides that are making their way into flowers given their watering and pesticide regimes, and consider alternative management practices that reduce harm to bees and the ecosystems dependent on them.

“It’s not as simple as ‘don’t use pesticides’ — sometimes they’re necessary,” Cecala said. “However, people can look for a different class of insecticide, try to apply them on plants that aren’t attractive to bees, or find biological methods of pest control.”

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Baby marine turtles’ stomachs are full of harmful plastic debris

Plastic pollution has become one of the most pressing threats to marine wildlife. It is estimated that more than 700 marine species, from blue whales to small barnacles, have had interactions with plastics in the oceans. Plastics now make up 80% of all marine debris and can be found everywhere, from surface waters to deep-sea sediments. Plastics in the oceans come in the form of macroplastics (>1mm) and microplastics (<1mm).

A new study published in Frontiers in Marine Science shows that small juvenile marine turtles from the Indian Ocean and Pacific Ocean have a very high incidence of plastic ingestion.

Plastic ingestion and entanglement (which can cause suffocation) has now been documented for every species of marine turtle. Small juvenile turtles are thought to be most at risk, as this life stage is most prone to entanglement and ingestion due to their feeding preferences, while the oceanic zones they inhabit overlap with areas of high plastic pollution.

Ingestion of plastic is thought to lead to mortality through laceration, obstruction, or perforation of the gastrointestinal tract. It is also suspected to lead to malnutrition and chemical contamination.

Plastic ingestion by sea turtles

To study just how much and what type of plastics are ingested by small juvenile turtles, researchers examined the contents of the stomach, intestines, cloaca and bladder of stranded or bycaught specimens from the Indian Ocean off Western Australia and the Pacific Ocean off Eastern Australia. They looked for plastics inside green (36 in the Pacific and 22 in the Indian Ocean), loggerhead (7 and 14), olive ridley (seven in the Pacific), hawksbill (five and two), and flatback turtles (10 and 18). They classified plastics according to color and type (for example, hard plastics, rope, or plastic bags) and identified the sources of plastic polymers found.

Plastics were only found in the gastrointestinal tract. The amount of plastics (>1mm) that were ingested varied by oceans and by species. The highest number of ingested plastic pieces occurred in green turtles: one animal in the Indian Ocean contained 343 pieces, and one animal in the Pacific Ocean contained 144. No plastic ingestion was found in sampled hawksbill turtles from either ocean, but this might have been due to the small sample size.

The proportion of turtles that had ingested plastic was much higher in the Pacific Ocean than in the Indian Ocean. From the specimens collected from the Pacific Ocean, green turtles were most likely to contain plastics (83%), followed by loggerheads (86%), flatbacks (80%), and olive ridleys (29%). On the other hand, from the specimens from the Indian Ocean, the flatback turtles contained the most plastics (28%), followed by loggerheads (21%) and green turtles (9%).

For green turtles in the Pacific Ocean, from 0% to 0.9% of the total body mass was ingested plastic, and from 0% to 2% for flatback turtles in the Indian Ocean.

The types of plastic also varied between the two study sites. “Plastic in the Pacific turtles was mostly hard fragments, which could come from a vast range of products used by humans, while Indian Ocean plastics were mostly fibers – possibly from fishing ropes or nets,” says lead author Dr Emily Duncan of the University of Exeter.

A novel evolutionary trap

The researchers bring attention to the potential evolutionary trap that plastic pollution has created for juvenile turtles. An evolutionary trap occurs when a previously adaptive behavior or habitat now has negative effects on overall survival and reproduction.

Post-hatchling turtles have adapted to enter the oceanic zone (for green, loggerhead, hawksbill, and olive ridley turtles) or neritic waters (flatback turtles) where they feed and grow into maturity. Normally, these habitats are ideal for their development, but the rapid introduction of plastic debris has made them risky for juvenile turtles.

Actions to mitigate and prevent plastic pollution are necessary. “The polymers most commonly ingested by turtles in both oceans were polyethylene and polypropylene. These polymers are so widely used in plastic products that it’s impossible to pin down the likely sources of the fragments we found, so interventions are needed to stop plastic pollution from land-based sources,” says Duncan.

“The next stage of our research is to find out if and how plastic ingestion affects the health and survival of these turtles. This will require close collaboration with researchers and veterinarians around the world.”

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Cutting 250 calories daily and exercising may improve heart health in obese older adults

Cutting just 250 calories a day with moderate exercise reaped bigger rewards than exercise alone for older, obese adults. Among older adults with obesity, combining aerobic exercise with a moderate reduction in daily calories resulted in greater improvements in aortic stiffness (a measure of vascular health, which impacts cardiovascular disease), compared to exercise only or to exercise plus a more restrictive diet, according to new research published today in the American Heart Association’s flagship journal Circulation.

Modifiable lifestyle factors such as a healthy diet and regular physical activity may help offset age-related increases in aortic stiffness. Although aerobic exercise generally has favorable effects on aortic structure and function, previous studies have shown that exercise alone may not be sufficient to improve aortic stiffness in older adults with obesity.

“This is the first study to assess the effects of aerobic exercise training with and without reducing calories on aortic stiffness, which was measured via cardiovascular magnetic resonance imaging (CMR) to obtain detailed images of the aorta,” said Tina E. Brinkley, Ph.D., lead author of the study and associate professor of gerontology and geriatric medicine at the Sticht Center for Healthy Aging and Alzheimer’s Prevention at Wake Forest School of Medicine in Winston-Salem, North Carolina. “We sought to determine whether adding caloric restriction for weight loss would lead to greater improvements in vascular health compared to aerobic exercise alone in older adults with obesity.”

This randomized controlled trial included 160 sedentary adults, ages 65–79 years with obesity (BMI=30–45 kg/m2). The average age of the participants was 69 years; 74% were female; and 73% were white. Participants were randomly assigned to one of three intervention groups for 20 weeks: 1) exercise only with their regular diet; 2) exercise plus moderate calorie restriction (reduction of approximately 250 calories/day); or 3) exercise plus more intensive calorie restriction (reduction of approximately 600 calories/day).

The two calorie-restricted groups received pre-made lunches and dinners with less than 30% of calories from fat and at least 0.8 grams of protein per kg of their ideal body weight, prepared under the direction of a registered dietitian for the study; they made their own breakfasts according to the dietitian-approved menu. Everyone in the study received supervised aerobic exercise training four days per week for the duration of the 20-week study at the Geriatric Research Center at Wake Forest School of Medicine.

The structure and function of the aorta were assessed with cardiovascular magnetic resonance imaging to measure aortic arch pulse wave velocity (PWV) (the speed at which blood travels through the aorta) and distensibility, or the ability of the aorta to expand and contract. Higher PWV values and lower distensibility values indicate a stiffer aorta.

The results found that weight loss of nearly 10% of total body weight or about 20 pounds over the five-month study period was associated with significant improvements in aortic stiffness — only in the participants assigned to the exercise plus moderate calorie restriction group. Additional findings include:

• The exercise plus moderate calorie restriction group had a 21% increase in distensibility and an 8% decrease in PWV.
• None of the aortic stiffness measures changed significantly in either the exercise-only group or the exercise plus more intensive calorie restriction group.
• Changes in BMI, total fat mass, percent body fat, abdominal fat and waist circumference were greater in both of the calorie-restricted groups compared to the exercise-only group.
• Weight loss was similar between the calorie-restricted groups despite nearly two times fewer calories (26.7% reduction in calories vs. a 14.2% reduction in calories) in the intensive calorie restriction group.

“Our findings indicate that lifestyle changes designed to increase aerobic activity and moderately decrease daily calorie intake may help to reduce aortic stiffness and improve overall vascular health,” said Brinkley. “However, we were surprised to find that the group that reduced their calorie intake the most did not have any improvements in aortic stiffness, even though they had similar decreases in body weight and blood pressure as the participants with moderate calorie restriction.”

Brinkley added, “These results suggest that combining exercise with modest calorie restriction — as opposed to more intensive calorie restriction or no-calorie restriction — likely maximizes the benefits on vascular health, while also optimizing weight loss and improvements in body composition and body fat distribution. The finding that higher-intensity calorie restriction may not be necessary or advised has important implications for weight loss recommendations to improve cardiovascular disease risk in older adults with obesity.”

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