Stressed, toxic, zombie cells seen for first time in Alzheimer's

August 22, 2018, University of Texas Health Science Center at San Antonio
Miranda Orr, Ph.D., of UT Health San Antonio, led research showing cell stress called senescence is present in Alzheimer's disease and is linked to tau protein tangles in the brain disorder. Credit: UT Health San Antonio

A type of cellular stress known to be involved in cancer and aging has now been implicated, for the first time, in Alzheimer's disease. UT Health San Antonio faculty researchers reported the discovery Monday [August 20, 2018] in the journal Aging Cell.

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

Cellular senescence allows the stressed cell to survive, but the cell may become like a zombie, functioning abnormally and secreting 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."

Improvements in brain structure and function

The team confirmed the discovery in four types of that model Alzheimer's disease. The researchers then used a combination of drugs to clear senescent cells from the brains of middle-aged Alzheimer's mice. The drugs 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, the findings were exciting. "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 (magnetic resonance imaging) 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. He also directs the VA-sponsored Geriatric Research, Education and Clinical Center (GRECC) in the South Texas Veterans Health Care System.

Typically, in testing an intervention in Alzheimer's mice, the therapy only works if mice are treated before the disease starts, Dr. Musi said.

Tau protein accumulation is responsible

In Alzheimer's disease, patient brain tissue accumulates tau protein tangles as well as another protein deposit called amyloid beta plaques. The team found that tau accumulation was responsible for . 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.

In other studies to confirm this, reducing tau genetically also reduced senescence. The reverse also held true. Increasing tau genetically increased senescence.

Importantly, the 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 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 . These drugs were able to clear the tau pathology."

Potentially a therapy to be tested 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 drugs specifically target—and therefore only kill—the . Because the drugs have a short half-life, they are cleared quickly by the body and no side effects were observed.

Dasatinib is an oral medication. The mice were treated with the combination every other week. "So in the three months of treatment, they only received the drug six times," Dr. 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."

Dosage and frequency in humans would need to be determined in clinical trials, she said.

Next, the researchers will study whether cell senescence is present in traumatic brain injury. TBI is a injury that develops tau protein accumulation and is a significant cause of disability in both military and non-military settings, Dr. Orr said.

Explore further: Senolytic drugs reverse damage caused by senescent cells in mice

More information: Nicolas Musi et al, Tau protein aggregation is associated with cellular senescence in the brain, Aging Cell (2018). DOI: 10.1111/acel.12840

Related Stories

Senolytic drugs reverse damage caused by senescent cells in mice

July 9, 2018
Injecting senescent cells into young mice results in a loss of health and function but treating the mice with a combination of two existing drugs cleared the senescent cells from tissues and restored physical function. The ...

Can nanotechnology help treat Alzheimer's?

June 19, 2018
Alzheimer's disease (AD) is the most common form of dementia. It takes a devastating toll on patients and family members, who are usually the caregivers. Current drugs only treat symptoms of AD, not its causes.

Alzheimer's disease might be a 'whole body' problem

October 31, 2017
Alzheimer's disease, the leading cause of dementia, has long been assumed to originate in the brain. But research from the University of British Columbia and Chinese scientists indicates that it could be triggered by breakdowns ...

Elimination of senescent cells improves lung function in mice

August 4, 2016
Most cells can divide only a limited number of times and eventually undergo permanent cell cycle arrest, a state known as cellular senescence. Cellular senescence is mediated by activation of specific cellular signaling pathways ...

Drug restores cells and memories in Alzheimer's mouse models

July 6, 2017
A new drug can restore memories and connections between brain cells in mice with a model of Alzheimer's disease, a new Yale-led study suggests.

New Alzheimer's animal model more closely mimics human disease

December 4, 2017
By injecting human Alzheimer's disease brain extracts of pathological tau protein (from postmortem donated tissue) into mice with different amounts of amyloid-β (Aβ) plaques in their brains, researchers from the Perelman ...

Recommended for you

Meditation and music may alter blood markers of cellular aging and Alzheimer's disease

November 13, 2018
A research team led by Dr. Kim Innes, a professor in the West Virginia University School of Public Health, has found that a simple meditation or music listening program may alter certain biomarkers of cellular aging and Alzheimer's ...

Alzheimer's and cardiovascular disease share common genetics in some patients

November 9, 2018
Genetics may predispose some people to both Alzheimer's disease and high levels of blood lipids such as cholesterol, a common feature of cardiovascular disease, according to a new study by an international team of researchers ...

Artificial intelligence predicts Alzheimer's years before diagnosis

November 6, 2018
Artificial intelligence (AI) technology improves the ability of brain imaging to predict Alzheimer's disease, according to a study published in the journal Radiology.

Diabetes medications may reduce Alzheimer's disease severity

November 1, 2018
People with Alzheimer's disease who were treated with diabetes drugs showed considerably fewer markers of the disease—including abnormal microvasculature and disregulated gene expressions—in their brains compared to Alzheimer's ...

Massive study confirms that loneliness increases risk of dementia

October 29, 2018
A new Florida State University College of Medicine study involving data from 12,000 participants collected over 10 years confirms the heavy toll that loneliness can take on your health: It increases your risk of dementia ...

Bioactive compound from the Rhodiola plant improves memory

October 25, 2018
In an ageing society, more people are suffering from memory disorders. The progressive loss of memory severely impairs the quality of life of those affected. So far, no drugs are known to prevent age-related cognitive decline.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.