Researchers from the Mayo Clinic have identified a new target in the battle against dementia and age-related cognitive decline – zombie cells. More formally known as senescent cells, these are cells that have stopped dividing but don't die, and tend to accumulate with age. The new research reveals that many pathological signs of neurodegenerative disease can be eliminated by removing these cells from the brain.
Senescent cells have been a hot area in anti-aging research over the past few years. Many scientists have been examining how the accumulation of these stagnant cells can be a fundamental trait of many age-related diseases. Prior work from the Mayo Clinic team in 2016 revealed a novel compound designed to eliminate senescent cells in mice resulted in the animals living longer and displaying reduced inflammation in fat, muscle and kidney tissue.
The latest study set out to examine the role of senescent cells in the progression of neurodegenerative disease. The team experimented with two different methods to clear senescent cells in mouse models. One method utilized a genetically engineered mouse designed to imitate Alzheimer's disease pathology by producing tangles of tau proteins in their neurons. This mouse model was subsequently engineered to be able to effectively clear senescent cells from its system when a specific chemical trigger was introduced.
"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," reveals Tyler Bussian, first author on the new study.
The other experiment found a novel experimental anticancer drug called navitoclax also functions as an effective senolytic agent, removing senescent cells from the mouse brains and successfully modulating the accumulation of tau proteins.
This novel discovery uncovers an exciting causal link between cellular senescence in the brain and the onset of neurodegenerative pathology. Even more interesting was the revelation that it wasn't the specific neurons becoming senescent that was preceding the tau protein clumping, but two other kinds of senescent brain cells – microglia and astrocytes.
"We had no idea whether senescent cells actively contributed to disease pathology in the brain, and to find that it's the astrocytes and microglia that are prone to senescence is somewhat of a surprise, as well," says senior author on the new study, Darren Baker.
Alzheimer's disease research has been in a state of flux over the past few years following a series of high-profile clinical trial failures with drugs designed to target the build-up of amyloid plaques in the brain, a popular hypothesis for the cause of the disease. Some scientists have been shifting their focus to other possible causative agents for neurodegenerative disease, including trying to home in on what occurs in the brain before these toxic proteins accumulate.
The new hypothesis outlined in the Mayo study is still in the very earliest stages of research, with this particular paper only examining how clearing senescent cells can prevent an accumulation of tau proteins. Further research is needed to understand if this technique can reverse any neurological damage after it has appeared, but that is certainly the next phase of work for the Mayo team.
"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," suggests Baker.
The tricky catch-22 that many Alzheimer's and dementia researchers are currently facing is that it is difficult to identify patients with early-stage dementia before degenerative symptoms appear, but it seems many prospective treatments may only be effective if applied during these pre-symptomatic stages. This latest study suggests that a build-up of specific senescent brain cells may offer an effective early-stage target in the battle against dementia, although it will surely still be several years before any effective clinical outcome can be applied in human subjects.
The new research was published in the journal Nature.
Source: Mayo Clinic