Culling Less Fit Neurons Protects against Amyloid-β-Induced Brain Damage and Cognitive and Motor Decline

Summary: Alzheimer’s disease (AD) is the most common form of dementia, impairing cognitive and motor functions. One of the pathological hallmarks of AD is neuronal loss, which is not reflected in mouse models of AD. Therefore, the role of neuronal death is still uncertain. Here, we used a Drosophila AD model expressing a secreted form of human amyloid-β42 peptide and showed that it recapitulates key aspects of AD pathology, including neuronal death and impaired long-term memory. We found that neuronal apoptosis is mediated by cell fitness-driven neuronal culling, which selectively eliminates impaired neurons from brain circuits. We demonstrated that removal of less fit neurons delays β-amyloid-induced brain damage and protects against cognitive and motor decline, suggesting that contrary to common knowledge, neuronal death may have a beneficial effect in AD. : Multicellular organisms eliminate abnormal but viable cells based on their fitness status through cell competition to maintain tissue integrity. Here, Coelho et al. report that fitness-based neuronal selection occurs in the course of neurodegeneration. Death of unfit neurons is beneficial, protecting against disease progression by restoring motor and cognitive functions. Keywords: cell fitness, neurodegeneration, apoptosis, β-amyloid, neuronal selection, Alzheimer’s, Drosophila, cell competition, azo