Tag Archives: Biochemistry and Molecular Biology

Study looks at whether daily limb compressions reduce dementia

A new study is looking at whether short, daily bouts of reduced blood flow to an arm or leg can reduce the ravages of dementia.

It’s called remote conditioning, and researchers say it activates natural protective mechanisms in the brain that should help about half of dementia patients.

The approach uses a blood pressure cuff-like device to temporarily restrict blood flow to an appendage repeatedly for a few minutes each day, which increases blood flow to other body areas, including the brain, said Dr. David Hess, Chairman of the Department of Neurology at the Medical College of Georgia at Georgia Regents University.

Increased flow activates endothelial cells lining blood vessels, calling to action a series of natural protective mechanisms that can be effective wherever blood travels, Hess said. Interestingly, the mechanisms seem most active in areas of impaired flow, such as those deep inside the brain, where most dementia has its roots.

“The most powerful way to protect the brain is to cut off blood flow to it for a short period of time to condition it,” said Hess. “What it does is elicit these protective pathways so when potentially lethal ischemia comes, you can survive it.” What it also appears to do is help permanently improve blood flow to these deep regions of the brain.

Age and being a female are two of the major risk factors for dementia. With nearly 15 percent of the U.S. population age 65 and older and half being female, Hess calls dementia a major health concern. “This is a big epidemic coming. This is a big killer and disabler, and everybody is concerned about this.”

A two-year, $750,000 translational grant from the National Institute of Neurological Disorders and Stroke should help Hess and his research team do the additional animal studies needed to move this safe and inexpensive technique for dementia to human studies.

“We think reduced cerebral blood flow, particularly in the deep white matter, is a major trigger of dementia,” Hess said. The white matter is primarily composed of axons, which connect neurons and different areas of the brain to each other and enable the brain to communicate with the body. The white protective coating on the axon is why this deep brain area is called white matter.

Hess, who is also a stroke specialist, says this area is particularly vulnerable to ischemia because the blood vessels that feed it are small and have long, tortuous routes. Strokes and/or impaired blood flow can lead to classic dementia symptoms such as forgetfulness and an unsteady gait.

By age 70, essentially everyone has some white matter disease, but in some it can be devastating. “You cannot go out in a car and find where you are going. You may not even be able to find your car. You can’t cook meals without setting the house on fire,” Hess said.

“What we want to do long term is find people who are at risk for dementia – they already have some white matter damage you can see on an MRI – then we condition them chronically with this device in their home,” Hess said. Chronically is a key word because, as with exercise, when this conditioning stops, so do its benefits. In fact, this passive therapy provides blood vessels many of the same benefits as exercise. “If you can exercise, you probably don’t need this,” Hess adds.

Previous studies in their animal model of vascular dementia have shown that just two weeks of daily, short bouts of ischemia to an appendage can improve the health of the important white matter. The new grant is allowing them to use a similar approach for periods of one and four months in older mice of both genders to better understand the mechanisms of action and how long and how often therapy is needed. While they don’t make as much as human, mice do make more amyloid, a protein that deposits in the brains of patients with Alzheimer’s, when brain blood flow is impaired. Mice make less with the conditioning, so the researchers also are looking further at that result.

A small intramural grant is enabling similar studies with a pig model in collaboration with University of Georgia colleagues Dr. Simon R. Platt, professor of neurology and neurosurgery in the College of Veterinary Medicine, and Dr. Franklin D. West, assistant professor in the College of Agricultural and Environmental Sciences.

While he notes that multiple natural mechanisms are activated, Hess and his team are focusing on how the temporary bouts of increased blood flow prompt endothelial cells to make the precursor for the blood vessel dilator nitric oxide.

“The enzyme that makes nitric oxide is upregulated and stimulated quickly,” Hess said. Nitric oxide gas has a short life, but when a lot is dumped in the blood, it’s oxidized into nitrite – the same stuff put in hot dogs – which circulates throughout the bloodstream so it goes wherever blood goes. Although just how this happens is unclear, when the nitrite gets to an area of low blood flow, it is converted back to nitric oxide, which helps improve flow, Hess said.

The MCG researchers are applying for federal funding to do trials in humans who are at high risk for stroke because of small vessel disease deep in the brain. In 2012, they published results of a small study in the journal Stroke indicating that successive, vigorous bouts of leg compressions following a stroke trigger natural protective mechanisms that reduce damage and double the effectiveness of the clot buster tPA. Similar studies have been done by others in patients with heart disease.

Vascular dementia is considered the second most common cause of dementia after Alzheimer’s disease, according to the Alzheimer’s Association. There are currently no drugs approved by the U.S. Food and Drug Administration specifically for vascular dementia.

Collaborators at MCG and GRU include Dr. Mohammad B. Khan, postdoctoral fellow in Dr. Hess’ lab; Dr. Nasrul Hoda, College of Allied Health Sciences; Dr. Philip Wang, Department of Psychiatry and Health Behavior; Dr. Ali Syed Arbab, Department of Biochemistry and Molecular Biology; Dr. Nathan Eugene Yanasak, Department of Radiology and Imaging;  and Dr. Jennifer Waller, Department of Biostatistics and Epidemiology.

Stress responder is a first responder in helping repair DNA damage and avoiding cancer

DNA damage increases the risk of cancer, and researchers have found that a protein, known to rally when cells get stressed, plays a critical, early step in its repair.

In the rapid, complex scenario that enables a cell to repair DNA damage or die, ATF3, or activating transcription factor 3, appears to be a true first responder, increasing its levels then finding and binding to another protein, Tip60, which will ultimately help attract a swarm of other proteins to the damage site.

“This protein is a so-called stress responder, so when a cell senses stress, such as DNA damage, this protein can be induced,” said Dr. Chunhong Yan, molecular biologist at the Georgia Regent University Cancer Center and the Department of Biochemistry and Molecular Biology at the Medical College of Georgia at GRU.

“One of the things we found is that ATF3 can bind to the Tip60 protein and promote the DNA damage repair function,” said Yan, corresponding author of the study published in the journal Nature Communications.

Like its partner Tip60, ATF3 is expressed at low levels until cells get stressed, and DNA mutation is one of the most common cell stressors. ATF3 then finds and binds to Tip60, increasing the usually unstable protein’s stability and level of expression. “If you look at the DNA under the microscope, you will see the damage site somehow labeled by this protein,” Yan said. Tip60, in turn, modifies the protein ATM, helping it form a sort of scaffold where other worker bee proteins soon assemble.

While it may take years for a cell to recognize DNA damage, once it does, the response occurs within minutes. One of the early arrivals to the ATM scaffold is p53, a known and powerful tumor suppressor. Once on the scene, p53 helps assess whether or not the damage is repairable. If not, it triggers cell suicide. If the damage is fixable, it will arrest cell proliferation and help start the repair.

There is clearly a protein connection. When researchers knock ATF3 down, Tip60 activation and ATM signaling both go down. Cells start accumulating DNA damage and become more vulnerable to additional stress, setting the stage for cancer and other problems. Previously there was no known relationship between ATF3 and Tip60.

Many factors, including sunlight, even chemotherapy, can cause DNA mutations. Mutations can even occur in the normal process of a cell multiplying, as cells do commonly in areas such as the skin and gastrointestinal tract, and tend to increase with aging. Cancer itself can cause additional mutations as it morphs to try to escape whatever treatment is being used against it. In fact, DNA repair likely is a constant in the body that works well most of the time. “That is why understanding DNA damage response is so important,” said Yan.

In human cancer cells, the researchers have shown that ATF3’s role precedes previously known steps. Future studies include finding a drug that could help cells make even more of this stress responder as a possible adjunct cancer therapy.

“We want to find a drug that can increase expression of this ATF3 in the body, and this increased ATF3 can promote Tip60 activity and overall promote cell response to DNA damage,” Yan said. The body naturally increases ATF3 levels in response to stress, including chemotherapy. In fact, many of the older cancer drugs intentionally damage DNA in an effort to promote cancer cell death. Now that ATF3’s connection to DNA repair has been made, that synergy likely explains another way chemotherapy works. However, additional study is needed to find a more targeted ATF3 activator without the numerous, known side effects of chemotherapy or other known stressors, Yan said.

While the protein ATF3 was known to be a stress responder, just how it responded has mostly remained a mystery. “We really don’t know much about this protein,” said Yan said. A decade ago, his research team found that ATF3 directly regulates the tumor suppressor p53.

“A next logical step is how can we make more ATF3?” While it’s not yet done clinically, in his lab, Yan has measured ATF3 levels in the tissue of cancer patients and found the levels are low and/or that the ATF3 gene itself is mutated. One day, measuring ATF3 levels might also help predict who is at highest risk for cancer, he said.

The research was funded by the National Institutes of Health. Postdoctoral Fellow, Dr. Hongmei Cui, is the study’s first author.