Scientists have demonstrated for the first time that neuronal cell death in Alzheimer’s disease (AD) may not be a bad thing. Experts at Champalimaud Centre for the Unknown (CCU) discovered that neuronal cell death may be the result of a cell quality control process that kicks in to protect the brain from the accumulation of malfunctioning neurons.
The researchers observed a cell quality control mechanism called “cell competition,” which enables a type of fitness comparison among neighboring cells. The fittest cells then trigger the suicide of the less fit cells around them. It has been recently established that this process of cell competition is a powerful anti-aging mechanism in the body, particularly in the brain.
“In 2015, we discovered that clearing unfit cells from a tissue was a very important anti-aging mechanism to preserve organ function,” said Eduardo Moreno, principal investigator of the CCU Cell Fitness lab. His team speculated that cell competition may also be involved in neurodegenerative diseases associated with accelerated aging, which had never been tested.
The investigation was focused on fruit flies that had been genetically modified to mimic the symptoms of Alzheimer’s disease in humans. The team manipulated fruit flies to express the amyloid-beta protein, which forms aggregates in the brains of AD patients.
The scientists set out to determine whether neuronal death was activated by the process of fitness comparison. In other words, Moreno said they wanted to confirm “that the neurons were not dying on their own but being killed by fitter neighbors.”
“When we started, the current view was that neuronal death must be always detrimental. And much to our surprise, we found that neuronal death actually counteracts the disease,” said study first author Dina Coelho.
When neuronal death was blocked in the brain of a fly, the insect developed even worse memory and motor coordination problems, died sooner, and experienced faster brain degeneration. On the other hand, when the fitness comparison process was boosted, the death of unfit neurons was accelerated and the flies expressing the AD-associated amyloid-beta proteins showed an impressive recovery.
“The flies almost behaved like normal flies with regard to memory formation, locomotive behavior, and learning,” explained Christa Rhiner.
This improvement came at a time when the flies were already strongly affected by AD symptoms, which means that the anti-aging mechanism keeps working well into the stages of Alzheimer’s disease. According to Moreno, the findings show that “the neuronal death protects the brain from more widespread damage and therefore the neuronal loss is not what is bad, it is worse not to let those neurons die.”
“Our most important finding is that we have probably been thinking the wrong way about Alzheimer’s disease,” said Moreno. “Our results suggest that neuronal death is beneficial because it removes neurons that are affected by noxious beta-amyloid aggregates from brain circuits, and having those dysfunctional neurons is worse than losing them.”
The study is published in the journal Cell Reports.