Posts Tagged Protein

[WEB SITE] Traumatic brain injuries could be healed using peptide hydrogels

Traumatic brain injury (TBI) –– defined as a bump, blow or jolt to the head that disrupts normal brain function –– sent 2.5 million people in the U.S. to the emergency room in 2014, according to statistics from the U.S. Centers for Disease Control and Prevention. Today, researchers report a self-assembling peptide hydrogel that, when injected into the brains of rats with TBI, increased blood vessel regrowth and neuronal survival.

The researchers will present their results at the American Chemical Society (ACS) Fall 2019 National Meeting & Exposition. ACS, the world’s largest scientific society, is holding the meeting here through Thursday. It features more than 9,500 presentations on a wide range of science topics.

“When we think about traumatic brain injuries, we think of soldiers and athletes,” says Biplab Sarkar, Ph.D., who is presenting the work at the meeting. “But most TBIs actually happen when people fall or are involved in motor vehicle accidents. As the average age of the country continues to rise, the number of fall-related accidents in particular will also increase.”

TBIs encompass two types of injuries. Primary injury results from the initial mechanical damage to neurons and other cells in the brain, as well as blood vessels. Secondary injuries, which can occur seconds after the TBI and last for years, include oxidative stress, inflammation and disruption of the blood-brain barrier. “The secondary injury creates this neurotoxic environment that can lead to long-term cognitive effects,” Sarkar says. For example, TBI survivors can experience impaired motor control and an increased rate of depression, he says. Currently, there is no effective regenerative treatment for TBIs.

Sarkar and Vivek Kumar, Ph.D., the project’s principal investigator, wanted to develop a therapy that could help treat secondary injuries.

We wanted to be able to regrow new blood vessels in the area to restore oxygen exchange, which is reduced in patients with a TBI. Also, we wanted to create an environment where neurons can be supported and even thrive.”

Biplab Sarkar, Ph.D., New Jersey Institute of Technology

The researchers, both at the New Jersey Institute of Technology, had previously developed peptides that can self-assemble into hydrogels when injected into rodents. By incorporating snippets of particular protein sequences into the peptides, the team can give them different functions. For example, Sarkar and Kumar previously developed angiogenic peptide hydrogels that grow new blood vessels when injected under the skin of mice.

To adapt their technology to the brain, Sarkar and Kumar modified the peptide sequences to make the material properties of the hydrogel more closely resemble those of brain tissue, which is softer than most other tissues of the body. They also attached a sequence from a neuroprotective protein called ependymin. The researchers tested the new peptide hydrogel in a rat model of TBI. When injected at the injury site, the peptides self-assembled into a hydrogel that acted as a neuroprotective niche to which neurons could attach.

A week after injecting the hydrogel, the team examined the rats’ brains. They found that in the presence of the hydrogel, survival of the brain cells dramatically improved, resulting in about twice as many neurons at the injury site in treated rats than in control animals with brain injury. In addition, the researchers saw signs of new blood vessel formation. “We saw some indications that the rats in the treated group were more ambulatory than those in the control group, but we need to do more experiments to actually quantify that,” Sarkar says.

According to Kumar, one of the next steps will be to study the behavior of the treated animals to assess their functional recovery from TBI. The researchers are also interested in treating rats with a combination of their previous angiogenic peptide and their new neurogenic version to see if this could enhance recovery. And finally, they plan to find out if the peptide hydrogels work for more diffuse brain injuries, such as concussions. “We’ve seen that we can inject these materials into a defined injury and get good tissue regeneration, but we’re also collaborating with different groups to find out if it could help with the types of injuries we see in soldiers, veterans and even people working at construction sites who experience blast injuries,” Kumar says.

via Traumatic brain injuries could be healed using peptide hydrogels

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[WEB SITE] Findings reveal how seizures can have lasting detrimental effects on memory

October 16, 2017

Although it’s been clear that seizures are linked to memory loss and other cognitive deficits in patients with Alzheimer’s disease, how this happens has been puzzling. In a study published in the journal Nature Medicine, a team of researchers reveals a mechanism that can explain how even relatively infrequent seizures can lead to long-lasting cognitive deficits in animal models. A better understanding of this new mechanism may lead to future strategies to reduce cognitive deficits in Alzheimer’s disease and other conditions associated with seizures, such as epilepsy.

“It’s been hard to reconcile how infrequent seizures can lead to persistent changes in memory in patients with Alzheimer’s disease,” said corresponding author Dr. Jeannie Chin, assistant professor of neuroscience at Baylor College of Medicine. “To solve this puzzle, we worked with a mouse model of Alzheimer’s disease focusing on the genetic changes that seizures might trigger in the memory center of the brain, the hippocampus, that could lead to loss of memory or other cognitive deficits.”

The researchers measured the levels of a number of proteins involved in memory and learning and found that levels of the protein deltaFosB strikingly increase in the hippocampus of Alzheimer’s disease mice that had seizures. DeltaFosB already is well known for its association with other neurological conditions linked to persistent brain activity of specific brain regions, such as addiction. In this study, the researchers found that after a seizure, the deltaFosB protein remains in the hippocampus for an unusually long time; its half-life – the time it takes for the amount of protein to decrease by half – is eight days. Most proteins have a half-life that is between hours and a day or two.

“Interestingly, because deltaFosB is a transcription factor, meaning that its job is to regulate the expression of other proteins, these findings led us to predict that the increased deltaFosB levels might be responsible for suppressing the production of proteins that are necessary for learning and memory,” Chin said. “In fact, we found that when the levels of deltaFosB increase, those of other proteins, such as calbindin, decrease. Calbindin also has been known for a long time to be involved in Alzheimer’s disease and epilepsy, but its mechanism of regulation was not known. We then hypothesized that deltaFosB might be regulating the production of calbindin.”

Further investigations supported the researchers’ hypothesis. The scientists showed that deltaFosB can bind to the gene calbindin suppressing the expression of the protein. When they either prevented deltaFosB activity or experimentally increased calbindin expression in the mice, calbindin levels were restored and the mice improved their memory. And when researchers experimentally increased deltaFosB levels in normal mice, calbindin expression was suppressed and the animals’ memory deteriorated, demonstrating that deltaFosB and calbindin are key regulators of memory.

Connecting pieces of the puzzle

“Our findings have helped us answer the question of how even infrequent seizures can have such lasting detrimental effects on memory,” Chin said. “We found that seizures can increase the levels of deltaFosB in the hippocampus, which results in a decrease in the levels of calbindin, a regulator of memory processes. DeltaFosB has a relatively long half-life, therefore even when seizures are infrequent, deltaFosB remains in the hippocampus for weeks acting like a brake, reducing the production of calbindin and other proteins, and disrupting the consequent brain activity involved in memory. The regulation of gene expression far outlasts the actual seizure event that triggered it.”

The scientists found the same changes in deltaFosB and calbindin levels in the hippocampus of Alzheimer’s disease patients and in the temporal lobe of epilepsy patients. However, they underscore that it is too soon to know whether regulating deltaFosB or calbindin could improve or prevent memory problems or other cognitive deficits in people with Alzheimer’s disease. However, “now that we know that the levels of deltaFosB and calbindin are effective markers of brain activity in the hippocampus and memory function, we propose that these markers could potentially help assess clinical therapies for Alzheimer’s and other diseases with seizures,” Chin said.

Source: Findings reveal how seizures can have lasting detrimental effects on memory

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