Organisms that favor survival and change to different circumstances will evolve, and this natural selection described by Charles Darwin defines biological evolution. The natural selection mechanism seems to have been adopted by the neurons in Alzheimer’s disease as well.
Neuronal loss, a distinctive characteristic of Alzheimer’s disease (AD) is often less understood as this pathological symptom is not replicated in mouse models of AD. For the first time, researchers from the Champalimaud Centre for the Unknown (CCU) in Lisbon, Portugal, have shown that Drosophila AD model replicates some common aspects of the disease pathosis, which includes neuronal death and long-term memory impairment. Studying the neuronal loss in this model, led their most exciting discovery that neuronal culling is a process by which less fit neurons are removed, which eventually protects the brain from further AD damage rather than aid in cognitive impairment. These neuronal quality control mechanisms observed in the fruit flies were published in the journal Cell Reports.
Much has been added to our understanding of AD’s clinical, pathological indications since its first appearance in the mid-60s. Although hypothesized that the β-amyloid-related toxicity mediates the neurodegeneration and the cognitive decline, concrete evidence is still lacking.
Eduardo Moreno, principal investigator of the Cell Fitness lab at the CCU, and his team studied AD in adult fruit fly’s that have been genetically modified by introducing the human β-amyloid in their brains. Moreno’s work published in 2015, first showed the cell competition observed in aging subjects and how it is a unique anti-aging mechanism that preserves organ function by eliminating the non-fit cells.
Building on these observations, they hypothesized that such survival mechanisms should also be present in neurodegenerative diseases that are often associated with aging. "This had never been tested," Moreno says. In collaboration with Christa Rhiner's Stem Cells and Regeneration lab at the CCU, they started by testing AD hallmarks in fruit fly models of the disease.
The genetically modified flies mimicked the AD symptoms and pathologies similar to those of AD patients: "they showed loss of long-term memory, accelerated aging of the brain and motor coordination problems, all of which got worse with age," specifies Christa Rhiner, whose team studied the cognitive and motor functions of the flies.
The first thing the scientists wanted to do was to see whether, in these flies, neuronal death was indeed activated by the process of fitness comparison—in other words, "that the neurons were not dying on their own but being killed by fitter neighbors," Moreno points out.
Image: Graphical abstract explaining the findings from Coelho et al. 2018.
"When we started, the current view was that neuronal death must always be detrimental. And much to our surprise, we found that neuronal death counteracts the disease," says Dina Coelho, first author of the study. Neuronal apoptosis blocking worsened the cognitive symptoms and motor coordination problems and eventually led to earlier deaths and faster brain degeneration.
However, when she boosted the fitness comparison process, thus accelerating the death of unfit neurons, the flies expressing the AD-associated amyloid-beta proteins showed an impressive recovery. "The flies almost behaved like normal flies about memory formation, locomotive behavior, and learning," says Rhiner, and this at a time point where the AD flies were already strongly affected.
The findings mean that the anti-aging mechanism in question keeps working well in Alzheimer's disease and shows that, in fact, "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," Moreno emphasizes. "Our most important finding is that we have probably been thinking the wrong way about Alzheimer's disease. 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" Moreno concludes.
The results could have significant therapeutical implications. "Some molecules have already been identified as potential inhibitors of cell suicide, and some experimental drugs exist and are being tested which inhibit those inhibitors of cell death, therefore accelerating neuronal death," says Moreno.
But he cautions: "This work has been done in fruit flies." It will be necessary to see, whether these results on neuronal death in Alzheimer's also hold for humans.
So, not every neuron you lose is a loss! Some could be for your benefit.
Watch this video for a simplistic explanation of Alzheimer’s Disease