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Eliminating ‘Zombie’ Brain Cells Could Prevent Alzheimer’s

By | September 19th, 2018

Inside your brain, there are 100 billion cells carrying out the daily tasks of keeping you alive and feeding you information: transmitting messages from one part of your brain to another, allowing you to process images, translating sound into meaning and moving your body. But over time, some cells stop being productive—their DNA becomes damaged and they’re no longer able to carry out their jobs. Sometimes these cells turn into tumors. Other times, they enter a ‘zombie’-like state called senescence. These are cells that have stopped dividing—in other words, they’ve retired. Everyone, if they live long enough, accumulates senescent cells. And now, scientists have found that getting rid of them might hold the clues to preventing Alzheimer’s.

Senescent cells don’t just kick back and float around like a new retiree on a lazy river. They accumulate in tissues and produce low levels of inflammation. In fact, some studies have shown that they’re behind age-related diseases like cataracts and arthritis. And these cells don’t just accumulate in the body—they also show up in the brain.

“Senescent cells are known to accumulate with advancing natural age and at sites related to diseases of aging, including osteoarthritis; atherosclerosis; and neurodegenerative diseases, such as Alzheimer’s and Parkinson’s,” said Darren Baker, Ph.D., a Mayo Clinic molecular biologist. “In prior studies, we have found that elimination of senescent cells from naturally aged mice extends their healthy life span.”

In this study, Baker took the model one step further: They used mice that are genetically engineered to have the hallmarks of Alzheimer’s disease. Then, they tried to wipe out the senescent, or so-called ‘zombie’ cells.

“We used a mouse model that produces sticky, cobweb like tangles of tau protein in neurons and has genetic modifications to allow for senescent cell elimination,” explains first author Tyler Bussian, a Mayo Clinic Graduate School of Biomedical Sciences student who is part of Dr. Baker’s lab. “When senescent cells were removed, we found that the diseased animals retained the ability to form memories, eliminated signs of inflammation, did not develop neurofibrillary tangles, and had maintained normal brain mass.”

The build-up of tau proteins is a hallmark of Alzheimer’s in the brain. Removing the senescent cells stopped tau from clumping and memories from deteriorating.

“Two different brain cell types called ‘microglia’ and ‘astrocytes’ were found to be senescent when we looked at brain tissue under the microscope,” says Bussian. “These cells are important supporters of neuronal health and signaling, so it makes sense that senescence in either would negatively impact neuron health.”

Researchers targeted senescent cells by engineering the mice to kill off their own retired cells when they were fed a certain chemical, and with a drug called navitoclax, originally created as a cancer drug. Navitoclax is still undergoing clinical trials and is not yet approved by the F.D.A.

The results are encouraging, but there are limitations to the study. It was conducted on mice engineered to produce high levels of tau, rather than beta-amyloid, which has long been the target of most drugs and is considered to be the driving factor of Alzheimer’s by many scientists. This approach was not tested in mice with beta-amyloid build-up, and animal results don’t always translate to humans. The senescent cells of the mice were eliminated before they started having memory problems, which would be tricky to carry out in humans.

“Clearly, this same approach cannot be applied clinically, so we are starting to treat animals after disease establishment and working on new models to examine the specific molecular alterations that occur in the affected cells,” said Baker.

This study was published in the journal Nature.

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