Biology subjects

Biglari, S.

Publications and source records attributed to Biglari, S..

4 recordsLinked to original sources

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↗

bioRxiv2026

Cell-specific variant-to-gene mapping identifies conserved neural and glial regulators of sleep

Excessive daytime sleepiness (EDS) is a heterogeneous phenotype with little known of its genetic basis. Large-scale genome-wide association studies (GWAS) have reported genomic loci associated with EDS, though since most of these are non-coding, the causal gene(s) underlying the association are not known. Additionally, the cell types in which these genes exert their effects on sleep have not been functionally explored in vivo. Here, we employed a chromatin-based variant-to-gene mapping approach to first implicate candidate effector genes at EDS GWAS loci in human-derived neural and glial cell lines. Subsequent cell type-specific RNAi knockdown of orthologous genes using neural and glial GAL4 drivers in Drosophila confirmed cell-specific regulation of sleep by these GWAS-implicated effector genes. Among these, ruby (ortholog to AP3B2), a component of the AP-3 vesicular trafficking complex emerged as a robust sleep regulator. Targeted knockdown in flies localized ruby function to astrocyte-like glia, where loss of ruby increased sleep duration. The conserved role of ruby/ ap3b2 was validated in zebrafish where CRISPR-mediated loss increased daytime sleep. Together, these findings show that physical variant-to-gene mapping predicted cell-type-specific gene function for complex sleep traits and revealed ruby/AP3B2 as a conserved glial regulator of sleep and arousal. This work provides a generalizable framework for connecting non-coding GWAS variants and their corresponding effector genes to identify novel and highly conserved regulators of sleep.

genetics↗

bioRxiv2025

The fat-body secreted neuropeptide CCHa2 signals insulin-producing cells in the brain to promote sleep

Sleep is a fundamental behavior regulated by diverse environmental and physiological cues. While the central mechanisms underlying sleep regulation have been investigated in detail, far less is known about how nutrient signals from the periphery are communicated to the brain to modulate sleep. Here, we perform a targeted RNAi screen of genes enriched in the fat body and regulated by feeding state to identify genes that function in the fat body to regulate sleep in Drosophila. This analysis found that body-specific knockdown of CCHa2 significantly reduced sleep duration and sleep depth in fed flies, phenocopying sleep in starved flies. CCHa2-deficient flies exhibited reduced glycogen stores and diminished feeding drive. Analysis of single-cell transcriptomic atlases confirms that the CCHa2 receptor (CCHa2-R) is selectively expressed in Insulin Producing Cells (IPCs) of the fly brain. We find that knockdown of CCHa2-R in IPCs recapitulates the sleep loss phenotype of CCHa2 mutants, supporting a role in adipose-brain signaling. Further screening of genes identified in single cell atlases as being enriched in IPCs led to the identification of numerous genes that function in IPCs to regulate sleep including modulators of wnt and insulin signaling. Together, these findings identify a fat body-IPC axis that is a critical modulator of sleep duration and intensity.

neuroscience↗

bioRxiv2025

Blood-derived dietary protein promotes sleep in the mosquito Aedes aegypti

Sleep is a ubiquitous, yet highly variable, behavior across species. The duration and timing of sleep are influenced by ecological demands and dietary context. In the mosquito Aedes aegypti, a blood-feeding insect with specialized nutritional requirements, the relationship between feeding and sleep remains poorly understood. Here, we investigated how blood-derived dietary protein influences sleep regulation. Using postural analysis, videography, and arousal-threshold assays, we established that immobility bouts of [≥]10 minutes reliably define sleep in Ae. aegypti. Mosquitoes lacking the circadian clock gene cycle still maintained daily sleep rhythms but exhibited reduced sleep duration and heightened overall activity. Infrared activity monitoring revealed that blood-fed females showed a marked increase in sleep beginning immediately after feeding and persisting for several days, accompanied by reduced locomotor activity. Notably, this sleep elevation lasted well beyond the cessation of previously reported host-seeking phases, raising the possibility of distinct phases of opportunistic versus targeted host pursuit. To determine the dietary basis of this effect, we tested mosquitoes fed a bovine serum albumin (BSA)-based diet. BSA feeding alone was sufficient to mimic the sleep-promoting and activity-reducing effects of blood, suggesting dietary protein is a major nutritional regulator. Moreover, RNAi-mediated knockdown of the leucokinin receptor (Lkr), which has previously been associated with fluid homeostasis and feeding behavior, resulted in enhanced sleep and reduced activity, implicating mosquito LK signaling in the modulation of postprandial sleep. Together, these findings demonstrate that blood-derived proteins drive sustained increases in sleep and reductions in locomotor activity in Ae. aegypti. This work positions Ae. aegypti as a model for dissecting nutrient-specific regulation of sleep and highlights potential adaptive functions of protein-induced quiescence, such as energy conservation and predator avoidance. More broadly, it provides insight into how specialized diets shape the neural and behavioral architecture of sleep.

neuroscience↗