New Insights into Brain Cell Death in Alzheimer’s and FTD

Scientists have found evidence of a previously unidentified process that might explain how brain cells die in Alzheimer’s disease and frontotemporal dementia (FTD). This discovery focuses on a mechanism called karyoptosis, which could guide researchers in developing new strategies to slow down the progression of these serious conditions.

Neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), Alzheimer’s, and FTD are often characterized by the accumulation of harmful proteins within neurons. Over time, this buildup leads to the death of nerve cells, which contributes to symptoms like memory loss. While various forms of cell death, including apoptosis, have been known for some time, they haven’t fully clarified the extensive neuron loss seen in these diseases.

Now, a team from King’s College London, in collaboration with the UK Dementia Research Institute and partly funded by Alzheimer’s Research UK, has pinpointed karyoptosis as a potential link between toxic protein buildup and the death of brain cells.

Karyoptosis involves a series of chemical reactions triggered by the accumulation of toxic proteins inside a cell. As this process occurs, the nucleus—a vital part of the cell that holds genetic material—gradually shrinks before ultimately disintegrating.

Findings in Alzheimer’s and FTD Patients

Research findings published in Nature Communications stem from an analysis of 3,000 brain cells taken from 28 individuals diagnosed with either FTD or end-stage Alzheimer’s disease. Utilizing computational algorithms, the researchers were able to identify various types of cell death happening within the tissue.

The analysis revealed that karyoptosis was evident in 35 percent of cells from the frontal cortex of Alzheimer’s patients, compared to only 15 percent in healthy older adults.

“This study represents the culmination of a decade of research at King’s, beginning when we identified karyoptosis in a less common disease,” a researcher noted, “to discovering its commonality in dementias affecting millions.”

A New Target for Treatment?

The researchers also identified a critical molecular pathway that seems to govern karyoptosis. They found that clumping of proteins inside neurons—a common feature of many neurodegenerative diseases—could initiate this harmful process.

According to the study, the buildup of these toxic proteins destabilizes the outer membrane of the nucleus, leading to its shrinkage and eventual breakdown.

The team explored proteins known as kinases, which function as molecular switches in this pathway. In laboratory tests using rat neurons, they discovered that inhibiting these switches lowered indicators associated with karyoptosis. Notably, the interaction between the kinase p38 MAP kinase and the protein LaminB1 appeared to be a promising target for slowing or even preventing nucleus breakdown.

The researchers are optimistic that this pathway might eventually lead to treatments that mitigate brain cell loss in dementia. Their next step is to devise methods to specifically target the interaction between p38 MAP kinase and LaminB1 in humans.

“By focusing on the connection between p38 MAP kinase and LaminB1, we might slow down cell death, allowing time for more precise therapies aimed at specific neurodegenerative diseases,” remarked a researcher from King’s College London.

Charting a Course for Future Therapies

“The loss of brain cells is a driving force behind many symptoms experienced by those living with dementia. Our research uncovers a new set of chemical events that can influence cell death in brain cells,” explained another researcher involved. “We’ve started to outline how karyoptosis functions, and I’m looking forward to the breakthroughs this may inspire within the dementia research community and beyond.”

“For years, we understood that toxic proteins accumulate in Alzheimer’s disease and FTD. However, how they lead to brain cell loss has remained somewhat of a puzzle,” she added. “Identifying karyoptosis is a significant step toward locating treatment targets that could halt or reduce cell loss. This might provide a wider window for therapies tackling the root causes of these diseases, bringing us closer to finding a cure for dementia.” This is why funding and support for research are so vital.

The study titled “Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress” was published in Nature Communications.