The proteins TREM2 and IL-33 are important to the ability of the brain’s immune cells to literally consume dead cells and other debris like the beta-amyloid plaque that piles up in patients’ brains, and levels of both are decreased in Alzheimer’s.

The investigators report for the first time that CBD normalizes levels and function, improving cognition as it also reduces levels of the immune protein IL-6, which is associated with the high inflammation levels found in Alzheimer’s, says Dr. Babak Baban, immunologist and associate dean for research in the Dental College of Georgia and the study’s corresponding author.

There is a dire need for novel therapies to improve outcomes for patients with this condition, which is considered one of the fastest-growing health threats in the United States, DCG and Medical College of Georgia investigators write in the Journal of Alzheimer’s Disease.

“Right now we have two classes of drugs to treat Alzheimer’s,” says Dr. John Morgan, neurologist and director of the Movement and Memory Disorder Programs in the MCG Department of Neurology. One class increases levels of the neurotransmitter acetylcholine, which also are decreased in Alzheimer’s, and another works through the NMDA receptors involved in communication between neurons and important to memory. “But we have nothing that gets to the pathophysiology of the disease,” says Morgan, a study coauthor.

The DCG and MCG investigators decided to look at CBD’s ability to address some of the key brain systems that go awry in Alzheimer’s.

They found CBD appears to normalize levels of IL-33, a protein whose highest expression in humans is normally in the brain, where it helps sound the alarm that there is an invader like the beta-amyloid accumulation. There is emerging evidence of its role as a regulatory protein as well, whose function of either turning up or down the immune response depends on the environment, Baban says. In Alzheimer’s, that includes turning down inflammation and trying to restore balance to the immune system, he says.

That up and down expression in health and disease could make IL-33 both a good biomarker and treatment target for disease, the investigators say.

CBD also improved expression of triggering receptor expressed on myeloid cells 2, or TREM2, which is found on the cell surface where it combines with another protein to transmit signals that activate cells, including immune cells. In the brain, its expression is on the microglial cells, a special population of immune cells found only in the brain where they are key to eliminating invaders like a virus and irrevocably damaged neurons.

Low levels of TREM2 and rare variations in TREM2 are associated with Alzheimer’s, and in their mouse model TREM2 and IL-33 were both low.

Both are essential to a natural, ongoing housekeeping process in the brain called phagocytosis, in which microglial cells regularly consume beta amyloid, which is regularly produced in the brain, the result of the breakdown of amyloid-beta precursor protein, which is important to the synapses, or connection points, between neurons, and which the plaque interrupts.

They found CBD treatment increased levels of IL-33 and TREM2 — sevenfold and tenfold respectively.

CBD’s impact on brain function in the mouse model of early onset Alzheimer’s was assessed by methods like the ability to differentiate between a familiar item and a new one, as well as observing the rodents’ movement.

People with Alzheimer’s may experience movement problems like stiffness and an impaired gait, says Dr. Hesam Khodadadi, a graduate student working in Baban’s lab. Mice with the disease run in an endless tight circle, behavior which stopped with CBD treatment, says Khodadadi, the study’s first author.

Next steps include determining optimal doses and giving CBD earlier in the disease process. The compound was given in the late stages for the published study, and now the investigators are using it at the first signs of cognitive decline, Khodadadi says. They also are exploring delivery systems including the use of an inhaler that should help deliver the CBD more directly to the brain. For the published studies, CBD was put into the belly of the mice every other day for two weeks.

A company has developed both animal and human inhalers for the investigators who also have been exploring CBD’s effect on adult respiratory distress syndrome, or ARDS, a buildup of fluid in the lungs that is a major and deadly complication of COVID-19, as well as other serious illnesses like sepsis and major trauma. The CBD doses used for the Alzheimer’s study were the same the investigators successfully used to reduce the “cytokine storm” of ARDS, which can irrevocably damage the lungs.

Familial disease is an inherited version of Alzheimer’s in which symptoms typically surface in the 30s and 40s and occurs in about 10-15% of patients.

CBD should be at least equally effective in the more common, nonfamilial type Alzheimer’s, which likely have more targets for CBD, Baban notes. They already are looking at its potential in a model of this more common type and moving forward to establish a clinical trial.

Plaques as well as neurofibrillary tangles, a collection of the protein tau inside neurons, are the main components of Alzheimer’s, Morgan says. Beta-amyloid generally appears in the brain 15-20 years or more before dementia, he says, and the appearance of tau tangles, which can occur up to 10 years afterward, correlates with the onset of dementia. There is some interplay between beta amyloid and tau that decrease the dysfunction of each, Morgan notes.

The Food and Drug Administration is scheduled to make a ruling by early June on a new drug aducanumab, which would be the first to attack and help clear beta amyloid, Morgan says.

Other coauthors include Drs. David Hess, neurologist and MCG dean, and MCG neuroscientists Kumar Vaibhav and Krishnan Dhandapani. The research was supported by the National Institutes of Health.

Engineers commonly produce heterostructures to achieve new device properties that are not available in a single material. A van der Waals heterostructure is one made of 2D materials that are stacked directly on top of each other like Lego-blocks or a sandwich. The van der Waals force, which is an attractive force between uncharged molecules or atoms, holds the materials together.

According to Slava V. Rotkin, Penn State Frontier Professor of Engineering Science and Mechanics, the one-dimensional van der Waals heterostructure produced by the researchers is different from the van der Waals heterostructures engineers have produced thus far.

“It looks like a stack of 2D-layered materials that are rolled up in a perfect cylinder,” Rotkin said. “In other words, if you roll up a sandwich, you keep all the good stuff in it where it should be and not moving around, but in this case you also make it a thin cylinder, very compact like a hot-dog or a long sushi roll. In this way, the 2D-materials still contact each other in a desired vertical heterostructure sequence while one needs not to worry about their lateral edges, all rolled up, which is a big deal for making super-small devices.”

The team’s research, published in ACS Nano, suggests that all 2D materials could be rolled into these one-dimensional heterostructure cylinders, known as hetero-nanotubes. The University of Tokyo researchers recently fabricated electrodes on a hetero-nanotube and demonstrated that it can work as an extremely small diode with high performance despite its size.

“Diodes are a major type of device used in optoelectronics — they are in the core of photodetectors, solar cells, light emitting devices, etc.,” Rotkin said. “In electronics, diodes are used in several specialized circuits; although the main element of electronics is a transistor, two diodes, connected back-to-back, may serve as a switch, too.”

This opens a potential new class of materials for miniaturized electronics.

“It brings device technology of 2D materials to a new level, potentially enabling a new generation of both electronic and optoelectronic devices,” Rotkin said.

Rotkin’s contribution to the project was to solve a particularly challenging task, which was ensuring that they were able to make the one-dimensional van der Waals heterostructure cylinder have all the required material layers.

“Using the sandwich analogy again, we needed to know whether we had a shell of ‘roast beef’ along the entire length of a cylindrical sandwich or if there were regions where we have only ‘bread’ and ‘lettuce’ shells,” Rotkin said. “Absence of a middle insulating layer would mean we failed in device synthesis. My method did explicitly show the middle shells were all there along the entire length of the device.”

In regular, flat van der Waals heterostructures, confirming existence or absence of some layers can be done easily because they are flat and have a large area. This means a researcher can use various type microscopies to collect a lot of signal from the large, flat areas, so they are easily visible. When researchers roll them up, like in the case of a one-dimensional van der Waals heterostructure, it becomes a very thin wire-like cylinder that is hard to characterize because it gives off little signal and becomes practically invisible. In addition, in order to prove the existence of insulating layer in the semiconductor-insulator-semiconductor junction of the diode, one needs to resolve not just the outer shell of the hetero-nanotube but the middle one, which is completely shadowed by the outer shells of a molybdenum sulfide semiconductor.

To solve this, Rotkin used a scattering Scanning Near-field Optical Microscope that is part of the Material Research Institute’s 2D Crystal Consortium, which can “see” the objects of nanoscale size and determine their materials optical properties. He also developed a special method of analysis of the data known as hyperspectral optical imaging with nanometer resolution, which can distinguish different materials and, thus, test the structure of the one-dimensional diode along its entire length.

According to Rotkin, this is the first demonstration of optical resolution of a hexagonal boron nitride (hBN) shell as a part of a hetero-nanotube. Much larger pure hBN nanotubes, consisting of many shells of hBN with no other types of material, were studied in the past with a similar microscope.

“However, imaging of those materials is quite different from what I have done before,” Rotkin said. “The beneficial result is in the demonstration of our ability to measure the optical spectrum from the object, which is an inner shell of a wire that is just two nanometers thick. It’s comparable to the difference between being able to see a wooden log and being able to recognize a graphite stick inside the pencil through the pencil walls.”

Rotkin plans to expand his research to extend hyperspectral imaging to better resolve other materials, such as glass, various 2D materials, and protein tubules and viruses.

“It is a novel technique that will lead to, hopefully, future discoveries happening,” Rotkin said.

These new details on the daily life of the highly sought-after migratory fish can help better manage their populations and provide scientists with new information to understand the impacts to the animal from changing environmental conditions.

To uncover these important details about the behaviors of mahi-mahi, or dolphinfish, the research team tagged captive spawning fish located at the UM Experimental Hatchery to build predictive spawning models and then used the models with data collected from mahi-mahi tagged in the wild. The study is the first to use acceleration data from remotely transmitting pop-up satellite tags to predict the spawning habitat of a wild marine fish. The UM Experimental Hatchery is the only place in the country where spawning mahi-mahi are kept in captivity.

To build the predictive models, the research team tagged five spawning mahi-mahi (Coryphaena hippurus) at the UM Hatchery and waited overnight to record the timing of when they spawned. In total, 40 individual spawning events were tracked in captivity. Then, they paired the acceleration data collected from the tags with the exact time of spawning to estimate when the animals would spawn in the wild.

To test the models’ capability to estimate where and when the fish spawned in the wild, the researchers tagged 17 wild mahi-mahi off the coast of Miami and two in the Gulf of Mexico.

From an analysis of the satellite tag data, the researchers found that wild mahi-mahi spawn at night, primarily during a new moon at depths greater than they would normally be. The Florida Straits appeared to be an important spawning habitat for mahi-mahi, although the models suggest that some limited spawning takes place further north.

They found that mahi-mahi typically go deeper in the water column at night and are more surface oriented during the day. However, the phase of the moon had an effect on their nighttime depth distribution with a full moon bringing mahi-mahi closer to the surface at night.

They also found that mahi-mahi use behavioral thermoregulation to stay between a relatively narrow temperature window of about 27-28 degrees Celsius (80 — 82 degrees Fahrenheit). When surface waters are warmer, they move deeper and swim northward with the Gulf Stream to regulate their temperature, while fish tagged in cooler months stayed primarily in surface waters and migrated east and west between Florida and the Bahamas, rather than swimming north. They were also found to be the most active at cooler temperatures and in warm waters during a full moon at night.

“Mahi-mahi are highly sought after by recreational and commercial fisheries and are economically important,” said Lela Schlenker, an alumna of the UM Rosenstiel school and lead author of the study. “It is critical to understand their migrations and the frequency, timing, and location of where they reproduce as well as how changing environmental conditions — like warmer oceans — might affect them to manage their populations sustainably now and in the future.”

The team also found from the satellite tag data that the wild mahi-mahi travel long distances — up to 107 kilometers (105 miles) per day and dive to depths of 250 meters (820 feet).

“Together these findings suggest that as climate change continues to warm ocean waters, mahi-mahi will likely continue to shift northward and deeper throughout their migrations,” said Martin Grosell,” professor and chair of the Department of Marine Biology and Ecology at the UM Rosenstiel School. “This is important for recreational and commercial landings of mahi-mahi and the ecology of pelagic ecosystems. A fruitful collaboration between scientists from three departments at the Rosenstiel School, as well as colleagues from University of Massachusetts, Dartmouth and access to healthy spawning mahi-mahi in captivity revealed new information about these valuable fish,” said Grosell.