The results of research in genetically modified fruit flies is challenging the widespread belief that neuronal cell death in Alzheimer’s disease (AD) is inevitably detrimental, a finding that could have important therapeutic implications. The studies, by a team at the Champalimaud Centre for the Unknown (CCU), in Lisbon, Portugal, suggest that a cell quality control process known as cell competition—through which substandard or abnormal cells in the brain and other tissues are eliminated—has a beneficial effect in AD, acting to remove toxic peptide-expressing neurons and so helping to hold back or protect against disease progression. Tests showed that blocking this natural cell culling process in the fruit fly model of AD resulted in worse symptoms and accelerated neurodegeneration.

“Our most important finding is that we have probably been thinking the wrong way about Alzheimer’s disease,” said Eduardo Moreno, Ph.D., who is principal investigator of the Cell Fitness lab at the CCU. “Our results suggest that neuronal death is beneficial because it removes neurons that are affected by noxious β-amyloid aggregates from brain circuits, and having those dysfunctional neurons is worse than losing them.” The team concluded, “Death of unfit neurons is beneficial, protecting against disease progression by restoring motor and cognitive functions.” Their report is titled, “Culling Less Fit Neurons Protects against Amyloid-β-Induced Brain Damage and Cognitive and Motor Decline.”

Beneficial neuronal death in Alzheimer's disease graphical abstract
Beneficial neuronal death in Alzheimer’s disease

Multicellular organisms have evolved mechanisms to help maintain tissue homeostasis and integrity throughout development and aging. One of these mechanisms, cell competition, effectively leads to the selection of the fittest cells in a tissue by enabling a “fitness comparison” between neighboring cells, which leads to the least fit cells undergoing suicide. Cell competition represents a key anti-aging mechanism throughout the body, and particularly in the brain. “In 2015, we discovered that clearing unfit cells from tissue was a very important anti-aging mechanism to preserve organ function,” said Dr. Moreno.

Neuronal cell loss is a key symptom of the neurodegenerative disorder AD, a progressive neurodegenerative disorder that eventually leads to severe cognitive impairment, behavioral changes, and walking difficulties. The disease is characterized by brain deposits of extracellular amyloid plaques, and by intracellular fibrils of hyperphosphorylated tau protein. It is widely believed that β-amyloid-related toxicity is the primary cause of disease, although, as the researchers wrote, “the mechanisms mediating amyloid-induced neurodegeneration and cognitive decline have not been fully elucidated.” Scientists also haven’t been able to study the mechanisms of AD-related neuronal cell loss in vivo to any great extent, because mouse models of the disease show only very little neuronal death.

Dr. Moreno’s team reasoned that the same cell comparison mechanisms that act to clear substandard cells during normal aging could feasibly also be involved in diseases of accelerated aging, such as AD, Parkinson’s disease, or Huntington’s disease. “This had never been tested”, he said, so the scientists collaborated with Christa Rhiner, Ph.D.’s team at the CCU’s Stem Cells and Regeneration lab, to look more closely at the hallmarks of AD in a fruit fly model of the disease that expresses human amyloid-β protein, and which develop symptoms and brain pathologies that are similar to those in human AD patients. These transgenic animals “… showed loss of long-term memory, accelerated aging of the brain and motor coordination problems, all of which got worse with age,” noted Dr. Rhiner.

The team’s initial studies suggested that neuronal expression of amyloid-β in the flies neurons changed the cells’ fitness, and induced cell elimination. When the researchers then blocked this naturally occurring neuronal fitness process that culls the cells, the animals exhibited worse memory problems, worse motor coordination, and faster neurodegeneration and mortality. “When we started, the current view was that neuronal death must be always detrimental,” said Dina Coelho, Ph.D., first author of the researchers’ study. “And much to our surprise, we found that neuronal death actually counteracts the disease.”

In contrast, boosting the process of fitness comparison speeded the death of unfit neurons, which resulted in the recovery of the AD-modelling amyloid-β-expressing flies. “The flies almost behaved like normal flies with regard to memory formation, locomotive behavior, and learning” at a time point when the control AD flies were already strongly affected, Dr. Rhiner noted.

The researchers’ results suggest that cell competition is still active in AD, and can help to hold back disease progression by eliminating affected neurons. “Our results suggest that that the toxic effects of a given peptide correlate directly with the level of neuronal competition and death it induces,” the authors wrote.

“… 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,” Dr. Moreno suggested. He acknowledged that the team’s observations about neuronal cell death in the fruit fly AD model can’t directly be extrapolated to humans, so far more research will be needed.

Nevertheless, the results could have important clinical implications, he commented. “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. ”

“Surprisingly, we found that neuronal death had a beneficial effect against β-amyloid-dependent cognitive and motor decline,” the authors concluded. “This finding challenges the commonly accepted idea that neuronal death is detrimental at all stages of the disease progression. We found that most amyloid-induced neuronal apoptosis is beneficial and likely acts to remove damaged and/or dysfunctional neurons in an attempt to protect neural circuits from aberrant neuronal activation and impaired synaptic transmission.”

 

 

 

 

 

 

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