Alzheimer’s disease and frontotemporal dementia are among the most common causes of dementia.
These conditions slowly damage the brain, causing problems with memory, thinking, language, personality, and daily activities.
Scientists have known for many years that harmful proteins build up inside brain cells during these diseases. However, one important mystery has remained unsolved. Researchers have not fully understood exactly how these toxic proteins eventually kill brain cells.
Now, researchers from King’s College London, working with the UK Dementia Research Institute, believe they have found an important part of the answer.
Their study, published in Nature Communications, describes evidence for a newly recognized process of cell death called karyoptosis. The discovery could eventually help scientists develop treatments that slow the loss of brain cells in Alzheimer’s disease and frontotemporal dementia.
Every cell contains a nucleus, which acts as the cell’s control center. The nucleus stores DNA, the genetic instructions needed for the cell to survive and function. In healthy cells, the nucleus remains stable throughout the cell’s life. During karyoptosis, however, the nucleus begins to shrink before eventually breaking apart. Once this happens, the cell can no longer survive.
The researchers believe this process is triggered when toxic proteins build up inside nerve cells. Protein clumps are a well-known feature of Alzheimer’s disease, frontotemporal dementia and several other neurodegenerative diseases, including amyotrophic lateral sclerosis, also known as ALS.
These protein clumps interfere with normal cell function, but scientists have struggled to explain how they actually lead to widespread nerve cell death.
To investigate, the team used advanced computer analysis to examine about 3,000 brain cells collected from 28 people who had either frontotemporal dementia or end-stage Alzheimer’s disease.
They searched for different patterns of cell death. The results showed that about 35 percent of brain cells from the frontal cortex of people with Alzheimer’s disease carried markers of karyoptosis, compared with only 15 percent in healthy older adults.
The scientists then explored what controls this newly identified process. They discovered that protein clumping appears to make the outer membrane surrounding the nucleus unstable. This instability causes the nucleus to collapse and eventually fall apart. The team also identified important proteins called kinases that act like switches controlling this chain of events.
One kinase called p38 MAP kinase was found to interact with another protein known as LaminB1. When the researchers blocked this interaction in rat nerve cells grown in the laboratory, they reduced signs of karyoptosis. This finding suggests that medicines targeting this pathway might slow brain cell loss.
Although these experiments were performed in laboratory cells rather than patients, they provide an important starting point for future drug development. Researchers hope that slowing karyoptosis could give brain cells more time to survive while other treatments target the underlying causes of dementia.
The findings are exciting because current dementia treatments provide only limited symptom relief and do not stop brain cells from dying. A therapy that slows cell death itself could potentially work alongside future medicines that remove harmful proteins or reduce inflammation.
There are important limitations. The study does not prove that blocking karyoptosis will prevent dementia in people. Most experiments were carried out using donated brain tissue and laboratory models, so clinical trials will be needed before any treatment becomes available.
Researchers also need to determine whether this process occurs during the earliest stages of disease and whether it plays a role in other neurological disorders.
Overall, this research offers a fresh way of thinking about why brain cells die in dementia. By identifying a new pathway that links toxic protein buildup to nerve cell death, scientists have uncovered a promising target for future therapies.
While much more work lies ahead, the discovery provides hope that slowing brain cell loss may one day become part of treating Alzheimer’s disease and frontotemporal dementia.
Study analysis: This is a well-designed laboratory and tissue study that provides strong biological evidence for a new mechanism of cell death.
However, it is still early-stage research and does not demonstrate benefits in human patients. The discovery is important because it identifies a possible drug target, but years of further studies and clinical trials will be needed before it can change medical care.
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Source: King’s College London.
