Scientists have identified evidence of a previously unknown process that may explain how brain cells die in Alzheimer’s disease and frontotemporal dementia (FTD). The discovery, centered on a mechanism known as caryoptosis, could point researchers toward new ways to slow the progression of these devastating diseases.
Many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and FTD, are characterized by the accumulation of harmful proteins within neurons. Over time, these nerve cells die, contributing to memory loss and other symptoms. Although scientists have long known about various forms of cell death, including apoptosis, these mechanisms have never fully explained the extensive neuronal loss seen in these disorders.
Now, researchers at King’s College London, in collaboration with the Dementia Research Institute UK and supported in part by Alzheimer’s Research UK, have identified karyoptosis as a possible missing link connecting the build-up of toxic proteins with brain cell death.
Karyoptosis refers to a series of chemical reactions that are set in motion when toxic proteins accumulate inside a cell. As the process unfolds, the cell’s nucleus, which contains its genetic material, gradually withers before finally breaking down.
Evidence found in brains with Alzheimer’s and FTD
The findings, published in Nature CommunicationsThey are based on an analysis of 3,000 brain cells collected from 28 people with FTD or end-stage Alzheimer’s disease. Using computational algorithms, the researchers identified different forms of cell death that occur within the tissue.
They found signs of karyoptosis in 35 percent of the frontal cortex cells of people with Alzheimer’s disease, compared with only 15 percent of the cells of healthy older adults.
“This study is the culmination of a 10-year journey at King’s, from first identifying karyoptosis in a relatively rare disease to the discovery that it is a common feature of dementias affecting millions of people.”
A possible new target for dementia treatments
The researchers also discovered a key molecular pathway that appears to control karyoptosis. They found that forcing proteins within neurons to clump together, a hallmark of many neurodegenerative diseases, can trigger this destructive process.
According to the study, the accumulation of toxic proteins destabilizes the outer membrane of the nucleus, causing it to contract and eventually disintegrate.
The team then investigated proteins known as kinases, which act as molecular switches in this pathway. In laboratory experiments with rat neurons, blocking these switches reduced markers associated with karyoptosis. In particular, the interaction between the p38 MAP kinase and the LaminB1 protein emerged as a promising target to slow or prevent core degradation.
Researchers believe this pathway could eventually lead to therapies that reduce brain cell loss in dementia. Their next goal is to develop ways to selectively target the interaction between p38 MAP kinase and LaminB1 in humans.
“By specifically targeting the interaction between p38 MAP kinase and LaminB1, we can slow down the process of cell death, buying time for more targeted therapies against specific neurodegenerative diseases,” said Dr. Manolis Fanto, Professor of Functional Genomics at the Institute of Psychiatry, Psychology and Neuroscience, King’s College London.
Building a roadmap for future therapies
“Cell death and loss in the brain drives many symptoms experienced by people living with dementia. Our study uncovers a new series of chemical events that may coordinate cell death in brain cells. We have begun to lay out the roadmap for how karyoptosis works, and I am excited to see future advances that this may drive in the dementia research community and beyond,” said Dr. Rebecca Casterton, principal investigator at the UK Dementia Research Institute at King’s and first author of the paper.
“For decades, we have known that toxic proteins accumulate in Alzheimer’s disease and frontotemporal dementia, but it is unclear exactly how they lead to brain cell loss.
“Identifying caryoptosis is a crucial step towards finding targets for treatments that can stop or slow cell loss. It could help widen the window for therapies that address the underlying causes of the disease, bringing us closer to a cure for dementia. This is why Alzheimer’s Research UK funds and supports research,” said Dr Sara Rodrigues, senior research manager at Alzheimer’s Research UK.
The study, “Karyoptosis mediates cell death and neurodegeneration following proteotoxic stress,” was published in Nature Communications.
The research was primarily funded by Alzheimer’s Research UK and the International Biotechnology and Biological Sciences Research Council Association. Additional support came from a grant provided by the UK Medical Research Council and the UK Dementia Research Institute.