Scientists at the University of Texas have implicated a type of cellular stress for the first time as a player in Alzheimer’s disease. And their discovery could lead to treatments for more than 20 human brain diseases including Alzheimer’s and traumatic brain injury. One author of the study went as far as to say the treatment that researchers used on mice to rid them of the stressed cells actually stopped Alzheimer’s disease “in its tracks.”
Researchers at the The University of Texas Health Science Center at San Antonio, now called UT Health San Antonio® established a link between tau tangles and the stressed or senescent cells they found in Alzheimer’s-diseased tissue. Senescence is the process by which cells irreversibly stop dividing or growing without actually dying. Already proven to be involved in cancer and aging, tau protein accumulation is known to exist in 20 human brain diseases. “Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer’s disease, progressive supranuclear palsy (PSP), traumatic brain injury (TBI) and over twenty others,” the research paper notes.
Senescent cells are stressed. They are toxic. But they don’t die. They are, in effect, zombie cells. And what’s worse, these senescent cells accumulate in tissues and may contribute to tissue damage, inflammation and the development of various age-related and chronic diseases. The scientists at UT Health used senolytic drugs (agents that selectively destroy senescent cells or induce cell death) to clear the senescent cells and tau tangles in Alzheimer’s mice. In the end, their experiment improved both brain function and structure.
The researchers reported their findings in August in the journal Aging Cell.
Cellular stress is what happens to our cells in response to environmental stressors like temperature, exposure to toxins and mechanical damage.
According to an article from the Bosnian Journal of Basic Medical Sciences, different stressors trigger different cellular responses such as inducing cell repair, adaptation or remodeling or even triggering cell death. “Inability to repair the damage or exposure to prolonged stress may contribute to aging. Persistent cell stress often enhances susceptibility to cancer and aging-associated diseases,” writes article author, Borut Pojsak, of the University of Ljubljana in Slovenia. He said because cells and tissues are being used more and more for new therapies and transplantations, discovering how and why they respond to stress and ameliorating negative response is important in the prevention of all kinds of disorders that develop because of persistent stress.
Researchers at UT Health stated that they saw tau as an appealing molecular target for intervention because so many studies have indicated that the causes and effects of tau protein tangles may be associated with cell deterioration. They hypothesized that tau accumulation may activate cellular stress response, and thus initiate a chronic degenerative process that leads to loss of neurons and brain dysfunction. The UT researchers tested their hypothesis by looking at human brain tissue with Tau-containing neurofibrillary tangles (NFTs) and used genetically modified mice that develop tau. In addition, they genetically reduced NFTs and used senolytic drugs to get rid of senescent cells.
Though cellular senescence allows a stressed cell to survive, the cell may behave like a zombie. It can function abnormally and secrete toxic substances that kill cells around it. “When cells enter this stage, they change their genetic programming and become pro-inflammatory and toxic,” said study senior author Miranda E. Orr, Ph.D., VA research health scientist at the South Texas Veterans Health Care System, faculty member of the Sam and Ann Barshop Institute for Longevity and Aging Studies, and instructor of pharmacology at UT Health San Antonio. “Their existence means the death of surrounding tissue.”
The team confirmed the discovery in four types of mice that model Alzheimer’s disease, UT Health reported. “The researchers then used a combination of drugs to clear senescent cells from the brains of middle-aged Alzheimer’s mice. Such drugs are called senolytics. The drugs used by the San Antonio researchers are Dasatinib, a chemotherapy medication that is U.S. Food and Drug Administration-approved to treat leukemia, and Quercetin, a natural flavonoid compound found in fruits, vegetables and some beverages such as tea.”
After three months of treatment, UT Health said their findings were “exciting.” Orr said in a statement that the Alzheimer’s mice were 20 months old and had advanced brain disease when researchers started the therapy. “After clearing the senescent cells, we saw improvements in brain structure and function. This was observed on brain MRI studies (magnetic resonance imaging) and postmortem histology studies of cell structure. The treatment seems to have stopped the disease in its tracks,” she said.
“The fact we were able to treat very old mice and see improvement gives us hope that this treatment might work in human patients even after they exhibit symptoms of a brain disease,” stated Nicolas Musi, the study’s first author, professor of Medicine and director of the Sam and Ann Barshop Institute at UT Health San Antonio.
Illustration of a neuron affected by Alzheimers disease. Neuronal degeneration is linked to the build up of tau proteins (pink) between cells, as well as a build up of the beta-amyloid peptide outside the cells, causing amyloid plaques (the cluster top right).
“Alzheimer’s is linked to accumulations of beta-amyloid, which occurs early in the disease, and tau proteins, which occur later in the disease,” BioSpace reported. “The researchers found that the cell senescence was caused by the tau accumulation. They went on and compared Alzheimer’s mice that only had tau tangles with mice that only had amyloid beta. Senescence was only seen in the mice with tau tangles. They also confirmed that reducing tau genetically also reduced senescence, and vice versa.”
Senolytic drugs only target and only kill senescent cells. They are cleared quickly by the body, and researchers saw no side effects.
Mice were treated with a drug combination including Dasatinib every other week. “So in the three months of treatment, they only received the drug six times,” Orr said. “The drug goes in, does its job and is cleared. Senescent cells come back with time, but we expect that it would be possible to take the drug again and be cleared out again. That’s a huge benefit — it wouldn’t be a drug that people would have to take every day.”
Musi said he anticipates many further studies to understand the process using senolytic drugs. “Because these drugs are approved for other uses in humans, we think a logical next step would be to start pilot studies in people,” he said.