For decades, scientists studying Alzheimer’s disease have seen the same troubling pattern.
Harmful proteins collect inside brain cells, memory gets worse, thinking becomes more difficult, and millions of nerve cells eventually disappear. What has remained unclear is exactly how these protein buildups kill the cells.
Researchers at King’s College London, together with the UK Dementia Research Institute, now believe they have identified an important missing step. Their findings, published in Nature Communications, point to a newly described form of cell death called karyoptosis that may explain why so many brain cells are lost in Alzheimer’s disease and frontotemporal dementia.
Dementia is not a normal part of aging. It is caused by diseases that damage the brain over many years. Alzheimer’s disease is the most common form, while frontotemporal dementia often affects personality, behaviour, and language before memory.
In both diseases, nerve cells gradually stop working and eventually die. Since the brain cannot easily replace these lost cells, symptoms slowly become worse.
The newly identified process begins inside the cell’s nucleus, which stores the cell’s DNA. Normally, the nucleus remains strong and protected. During karyoptosis, however, it slowly shrinks and breaks apart. Once the nucleus is destroyed, the brain cell can no longer survive.
To understand how often this happens, scientists used computer programs to study around 3,000 individual brain cells taken from 28 donated brains. Some belonged to people with frontotemporal dementia and others to people who had advanced Alzheimer’s disease. They compared these cells with healthy brain tissue from older adults.
The researchers found evidence of karyoptosis in many more cells from people with dementia. Around one-third of cells from the frontal cortex of Alzheimer’s patients showed signs of this process, compared with only a much smaller proportion of healthy brain cells.
The team then searched for the molecular events responsible. They found that toxic protein clumps appear to weaken the protective outer layer surrounding the nucleus. This damage triggers a series of chemical reactions controlled by proteins known as kinases. One kinase called p38 MAP kinase worked together with LaminB1 to drive the destruction of the nucleus.
When scientists blocked this interaction in rat nerve cells grown in the laboratory, they reduced markers of karyoptosis. Although this was an early experiment, it suggests that medicines designed to interrupt this pathway might one day slow the death of brain cells.
This possibility is important because today’s dementia medicines do not stop the disease itself. Most available drugs only provide temporary improvement in symptoms. A treatment that keeps brain cells alive for longer could potentially delay disease progression and give future disease-modifying therapies a better chance to work.
Researchers caution that these findings should not be viewed as an immediate breakthrough for patients. The work was carried out using brain tissue, computer analysis, and laboratory cell experiments. Human trials have not yet begun, and many questions remain unanswered.
Even so, the study provides an important advance in understanding dementia biology. It connects toxic protein buildup with a specific sequence of events leading directly to brain cell death, something scientists have been trying to explain for many years.
Study analysis: This research is scientifically significant because it identifies a plausible mechanism linking toxic proteins to neuron loss and reveals a specific drug target. However, the findings remain preclinical.
Whether blocking karyoptosis will slow dementia in people remains unknown, and future animal studies and human clinical trials will be essential before any new treatment reaches patients.
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Source: King’s College London.
