Researchers at UT Health San Antonio have made an astounding discovery in Alzheimer’s research. A type of cellular stress long known to have a role in cancer and aging has now been implicated in Alzheimer’s disease. The discovery was reported in late August in the journal Aging Cell.

The team found that the stress, called cellular senescence, is associated with harmful tau protein tangles that are a hallmark of 20 human brain diseases, including Alzheimer’s and traumatic brain injury. The researchers identified senescent cells in postmortem brain tissue from Alzheimer’s patients and then found them in postmortem tissue from another brain disease, progressive supranuclear palsy.

What is cellular senescence?

 

Cellular senescence is the zombification of a cell, allowing the stressed cell to still live, albeit functioning abnormally, all the while secreting substances that kill the 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 and instructor of pharmacology at UT Health San Antonio. “Their existence means the death of surrounding tissue.”

 

Zombie cells cleared, improvement noted

 

The discovery was confirmed by studying four types of mice that model Alzheimer’s disease. Once identified, researchers used a combination of drugs to clear senescent cells from the brains of middle-aged Alzheimer’s mice. The drugs used were 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, the findings were thrilling. “The mice were 20 months old and had advanced brain disease when we started the therapy,” Dr. Orr said. “After clearing the senescent cells, we saw improvements in brain structure and function. This was observed on brain MRI studies and postmortem histology studies of cell structure. The treatment seems to have stopped the disease in its tracks.” “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,” said Nicolas Musi, M.D., study first author, who is Professor of Medicine and Director of the Sam and Ann Barshop Institute at UT Health San Antonio. This counteracts the typical pattern in testing Alzheimer’s intervention in mice. Usually the therapy is only successful if the mice are treated before signs of the disease, Dr. Musi reported.

Tau protein the culprit

As we’ve discussed here before, in Alzheimer’s disease, patient brain tissue accumulates tau protein tangles, as well as another protein deposit called amyloid beta plaques. The team concurred that tau accumulation was responsible for cell senescence. Researchers compared Alzheimer’s mice that had only tau tangles with mice that had only amyloid beta plaques. Senescence was identified only in the mice with tau tangles. It’s important to note that the drug combination reduced not only cell senescence but also tau tangles in the Alzheimer’s mice. This is a drug treatment that does not specifically target tau, but it nonetheless effectively reduced the tangle pathology, Dr. Orr said.

“When we looked at their brains three months later, we found that the brains had deteriorated less than mice that received placebo control treatment,” she said. “We don’t think brain cells actually grew back, but there was less loss of neurons, less brain ventricle enlargement, improved cerebral blood flow and a decrease in the tau tangles. These drugs were able to clear the tau pathology.”

Paving the way for therapy in humans

“This is the first of what we anticipate will be many studies to better understand this process,” Dr. Musi said. “Because these drugs are approved for other uses in humans, we think a logical next step would be to start pilot studies in people.” The upside of these drugs are they they are designed to specifically target, and thus only kill, the senescent cells. And because the drugs are cleared quickly by the body, no significant side effects were observed.

The mice in the study were treated with the dasatinib, an oral medication, and quercetin every other week. During the three months of treatment they only received the drug six times. The infrequency of administration and ease of taking a pill makes this a very appealing treatment, as it’s non-invasive and can be taken at home.

Studies did conclude that senescent cells came back over time. However, the expectation is that it would be possible to take the drug again and have similar results, though further testing is necessary. Next up for the researchers is an exploration of whether cell senescence is present in traumatic brain injury, a significant cause of dementia. Of course, as with all studies, discoveries and breakthroughs, more research is necessary before success can be claimed. But this is all a very exciting and positive prospect for human studies and the potential in halting this life altering — and ending — disease. To read more in-depth about the progression of Alzheimer’s disease, check out our last blog HERE!

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