Dietary Interventions Modulate Cell Competition and Locomotor Decline in an Alzheimer’s Disease Drosophila Model

Highlights: What are the main findings? Cell competition timing and efficiency, together with locomotion, can be modulated by dietary regimen, in a Drosophila Alzheimer’s Disease model Yeast-based diet potentiates Amyloid-β42 accumulation, triggering cell competition and locomotion decline Tissue fitness and diet can synergistically modulate the strength and profile of neuronal cell competition What are the implications of the main findings? Targeting neuronal cell competition through nutritional interventions may offer new avenues to modulate the course of neurodegeneration Conserved fitness-sensing pathways like Flower can provide tractable biomarkers and therapeutic approaches for neurodegenerative diseases Alzheimer’s Disease (AD) is a neurodegenerative disorder characterised by Amyloid-beta 42 (Aβ42) plaque accumulation and cognitive decline, with current treatments focused on symptomatic relief. Emerging therapeutics, such as dietary interventions, can modulate cognitive decline and delay AD progression. Our previous work in Drosophila melanogaster identified cell competition as a key mechanism that eliminates unfit neurons in an AD model, improving locomotion by removing the unfit neurons expressing flower^LoseB and ahuizotl (azot). Here, we explored how diet influences azot-dependent cell competition and locomotion in the AD model. Flies were fed with either a yeast-based diet (YBD) or a synthetic (SAA) diet for up to 28 days. In contrast to YBD, SAA delayed cell competition activation until day 21, coinciding with locomotion improvement and delayed Aβ formation. The overexpression of the human Flower (hFWE) isoforms in a Drosophila neuronal context revealed functional conservation: hFWE1 acted as the sole loser isoform, and hFWE2 as a winner isoform. With the YBD, forcing cell competition by expressing hFWE2 in the AD model led to an accumulation of unfit cells and promoted worse locomotion phenotypes over time compared to with the SAA diet. Our data highlights the complex interaction between diet, cell competition, and Aβ toxicity, offering new therapeutic insights.