The current consensus about Alzheimer's disease is that the death of neurons in the brain is responsible for the cognitive chaos caused by the disease. But a new study suggests that neuronal death may actually be a protective mechanism. The new results may contribute to new therapeutic approaches to Alzheimer's.
For the first time, scientists at the Champalimaud Center (CC) in Lisbon, Portugal, have shown that neuronal death in Alzheimer's disease (AD) may actually not be a bad thing – on the contrary, it could be the result of a mechanism of cellular quality control that tries to protect the brain from the accumulation of dysfunctional neurons.
These results, obtained in fruit flies genetically modified to mimic the symptoms of human AD, were published in magazine Cell reports.
The cellular quality control mechanism at play is called cell competition and serves to select the fittest cells in a given tissue in the body through a “cell vigor comparison” (in English, fitness comparison) between each cell and its neighbors. As a result, the fittest cells trigger the suicide of their less fit neighbors.
Recently, cellular competition has been proven to be a potent and normal anti-aging mechanism for the body in general and the brain in particular. “In 2015, we found that removing inappropriate cells from a tissue was a very important anti-aging mechanism to preserve organ function,” says Eduardo Moreno, principal investigator at the laboratory of CellFitness of the CC.
The team's starting point for this work was the fact that these comparisons of cellular vigor take place in the normal aging process and, following the same logic, may also be involved in neurodegenerative diseases associated with accelerated aging, such as Alzheimer's and Parkinson's diseases. and Huntington, explains Moreno.
“This had never been tested,” he adds. In collaboration with Christa Rhiner's Stem Cell and Regeneration Laboratory, also at CC, the scientists began by looking at the typical features of AD in fruit fly models of the disease.
To do this, they created genetically engineered fruit flies to express in their brain the human beta-amyloid protein, which forms aggregates in the brain of patients with Alzheimer's. The formation of beta-amyloid aggregates in the brain is a crucial step in the development of AD.
The researchers then confirmed that the transgenic flies had symptoms and characteristics similar to those of human patients: "the flies had long-term memory loss, accelerated brain aging and motor coordination problems, which worsened with age," says Christa Rhiner, whose team studied the cognitive and motor functions of flies.
The scientists' next step was to determine whether, in these flies, neuronal death was in fact activated by the cell quality matching process – in other words, to show “that neurons were not dying by themselves, but being eliminated by cells more apt neighbors,” emphasizes Moreno.
“When we started, the general consensus was that neuronal death is always harmful. Therefore, we were surprised to discover that neuronal death can actually be advantageous in the early stages of the disease”, says Dina Coelho, the study's first author.
What happened was that when this scientist blocked neuronal death in the fly brain, the insects developed even worse memory problems and motor coordination problems, died sooner and their brain deteriorated faster.
However, when the scientist stimulated the process of cell competition, thereby accelerating the death of dysfunctional neurons, the flies expressing the AD-associated beta-amyloid protein made an impressive recovery. “The flies behaved almost like normal flies when it comes to memory formation, locomotor behavior and learning,” says Rhiner. And more: this recovery took place when the flies were already very affected by the disease.
This means that, in Alzheimer's disease, the anti-aging mechanism in question continues to function correctly. And it shows that, in fact, “neuron death protects the brain from more generalized damage and that, therefore, the loss of neurons in this case is not that bad. It would be worse not to let these neurons die”, emphasizes Moreno.
“Our most significant finding is that we are probably thinking wrongly about Alzheimer's disease. Our work suggests that neuronal death is beneficial because it removes neurons affected by toxic beta-amyloid aggregates from the brain circuits – and that keeping these dysfunctional neurons is worse than losing them,” concludes Moreno.
The new results could have important therapeutic implications. “Some molecules have already been identified as potential inhibitors of cell suicide, and some experimental substances that block these cell death inhibitors – thus accelerating neuronal death – exist and are being tested,” says Moreno.
But the researcher warns: “this work was done on fruit flies”. It will therefore be necessary to verify whether the results on neuronal death in Alzheimer's disease are replicable in humans.
Author Champalimaud Center | Champalimaud Foundation
Science in the Regional Press – Ciência Viva
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