Eliminating dead-but-toxic cells occurring naturally in the brains of mice designed to mimic Alzheimer’s slowed neuron damage and memory loss associated with the disease, according to a study published Wednesday that could open a new front in the fight against dementia.The accumulation in the body of “zombie cells” that can no longer divide but still cause harm to other healthy cells, a process called senescence, is common to all mammals.
Scientists have long known that these dead-beat cells gather in regions of the brain linked to old age diseases ranging from osteoarthritis and atherosclerosis to Parkinson’s and dementia.
Prior research had also shown that the elimination of senescent cells in ageing mice extended their healthy lifespan.
But the new results, published in Nature, are the first to demonstrate a cause-and-effect link with a specific disease, Alzheimer’s, the scientists said.
But any treatments that might emerge from the research are many years down the road, they cautioned.
In experiments, a team led by Tyler Bussian of the Mayo Clinic in Rochester, Minnesota used mice genetically modified to produce the destructive, cobweb-like tangles of tau protein that form in the neurons of Alzheimer’s patients.
The mice were also programmed to allow for the elimination of “zombie” cells in the same region.
“When senescent cells were removed, we found that the diseased animals retained the ability to form memories, and eliminated signs of inflammation,” said senior author Darren Baker, also from the Mayo Clinic.
The mice likewise failed to develop Alzheimer’s signature protein “tangles”, and retained normal brain mass.
Keeping zombies at bay
A closer look revealed that the “zombies” belonged to a class of cells in the brain and spinal cord, called glia, that provide crucial support and insulation to neurons.
“Preventing the build-up of senescent glia can block the cognitive decline and neuro-degeneration normally experienced by these mice,” Jay Penney and Li-Huei Tsai, both from MIT, wrote in a comment, also in Nature.
Bussian and his team duplicated the results with pharmaceuticals, suggesting that drugs could one day slow or block the emergence of Alzheimer’s by keeping these zombie cells at bay.
“There hasn’t been a new dementia drug in 15 years, so it’s exciting to see the results of this promising study in mice,” said James Pickett, head of research at Alzheimer’s Society in London.
For Lawrence Rajendran, deputy director of the Dementia Research Institute at King’s College London, the findings “open up new vistas for both diagnosis and therapy for neurodegenerative diseases, including Alzheimer’s.”
Up to now, dementia research has been mostly focused on the diseased neurons rather than their neighboring cells.
“It is increasingly becoming clear that other brains cells play a defining role,” Rajendran added.
Several barriers remain before the breakthrough can be translated into a “safe, effective treatment in people,” Pickett and other said.
The elderly often have lots of harmless brain cells that look like the dangerous senescent cells a drug would target, so the molecule would have to be good at telling the two apart.
Researchers have identified a novel mechanism and a potential new therapeutic target for Alzheimer’s disease (AD), says a new study on mice.
Alzheimer’s is characterised by profound memory loss and synaptic failure. Although the exact cause of the disease remains unclear, it is well established that maintaining memory and synaptic plasticity requires protein synthesis.
The function of the synapse is to transfer electric activity (information) from one cell to another.
“Alzheimer’s is such a devastating disease and currently there is no cure or effective therapy for it,” said Tao Ma, Assistant Professor at Wake Forest School of Medicine in the US.
“All completed clinical trials of new drugs have failed, so there is clearly a need for novel therapeutic targets for potential treatments.”
For the study, the team has shown that AD-associated activation of a signaling molecule termed eEF2K leads to inhibition of protein synthesis.
Further, they wanted to determine if suppression of eEF2K could improve protein synthesis capacity, consequently alleviating the cognitive and synaptic impairments associated with the disease.
They used a genetic approach to repress the activity of eEF2K in Alzheimer’s mouse models.
The findings, published in the Journal of Clinical Investigation, showed that genetic suppression of eEF2K prevented memory loss in those animal models and significantly improved synaptic function.