Yeragi, E. | Search bioRxiv

bioRxiv2026

Progressive behavioral and cognitive decline in Drosophila harboring AD-associated APOE4 variants

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, and its incidence is rising rapidly with population aging. Pathologically, AD is characterized by the accumulation of amyloid-beta (Abeta) plaques and hyperphosphorylated Tau neurofibrillary tangles. Human genomic studies have identified numerous risk alleles, with the APOE4 variant representing the strongest and most common genetic risk factor, present in approximately 75 percent of AD patients. However, APOE4 is neither necessary nor sufficient to cause disease, suggesting that additional genetic and environmental factors contribute to AD pathogenesis. Emerging evidence highlights a central role for oxidized lipid metabolism in AD. Disruption of lipid metabolism leads to lipid accumulation, reactive oxygen species (ROS) toxicity, and neurodegeneration, suggesting that oxidative stress may be a critical factor in enhancing AD susceptibility. To systematically investigate APOE function in vivo, we tested humanized Drosophila expressing the human APOE3 or APOE4 variants in place of the Drosophila ortholog Glial Lazarillo (GLaz). The lifespan of APOE3 and APOE4 flies does not differ under standard housing conditions, but the lifespan of APOE4 flies is significantly reduced when exposed to the ROS-promoting drug rotenone, supporting a multi-hit model of disease pathogenesis. APOE4 flies exposed to rotenone exhibit several AD-associated phenotypes, including age-related memory loss and chemosensory deficits, supporting the use of this model to investigate AD pathogenesis. Furthermore, progressive AD-associated phenotypes are also observed in APOE4 flies maintained on an obesogenic diet, suggesting that enhanced disease susceptibility is not specific to rotenone-induced stress but reflects a broader vulnerability to metabolic challenges. Together, these findings establish a scalable model to dissect APOE-dependent mechanisms and identify therapeutic targets in AD.

genetics↗

bioRxiv2025

Early life sleep is associated with longevity in Drosophila

Sleep is a universal behavior that is critical for brain function and physiological homeostasis. While growing epidemiological and experimental evidence suggests reduced sleep quality is associated with negative health outcomes, the causal relationship between sleep loss and reduced longevity remains poorly understood. Here, we examine sleep across the lifespan and its relationship to longevity in Drosophila melanogaster. We examined the associations between numerous components of sleep at different life stages to longevity. Early life sleep, but not middle and late-life sleep, was positively associated with longevity. Age-dependent changes in sleep were consistent but accelerated, when flies are housed under stressful conditions including nutrient and temperature stress. Further, pharmacological restoration of sleep in the first 10 days of life, but not at later time points, increases longevity. Together, this work provides a systematic investigation of how different components of sleep impact longevity and suggests early life sleep may be particularly important in promoting sleep across the lifespan.

neuroscience↗