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

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 <i>Drosophila melanogaster</i> identified cell competition as a key mechanism that eliminates unfit neurons in an AD model, improving locomotion by removing the unfit neurons expressing <i>flower^LoseB</i> and <i>ahuizotl</i> (<i>azot</i>). Here, we explored how diet influences <i>azot</i>-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 <i>human Flower (hFWE)</i> isoforms in a <i>Drosophila</i> neuronal context revealed functional conservation: <i>hFWE1</i> acted as the sole loser isoform, and <i>hFWE2</i> as a winner isoform. With the YBD, forcing cell competition by expressing <i>hFWE2</i> 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.