Light Exposure Ameliorates Tau-Induced Deficits via Adenosine Signaling and Mitochondrial Quality Control in...

Background: Accumulating evidence suggests that environmental light cues influence brain function and neurodegenerative processes; however, the underlying cellular mechanisms remain incompletely understood. Methods: Here, using a Tau-overexpressing Drosophila model, we investigated how light exposure modulates neurodegeneration-associated phenotypes, with a particular focus on adenosine signaling and mitochondrial homeostasis. We performed behavioral assays, biochemical measurements, genetic interference targeting the adenosine receptor, and mito-QC reporter analysis to assess mitochondrial quality control. Results: We show that light exposure ameliorates Tau-induced behavioral impairments and neuropathological features, reducing climbing time by approximately 29% in males and 45% in females, and extending median lifespan by ~29% in males and ~26% in females. Notably, biochemical analyses revealed that light exposure significantly increases brain adenosine levels at ZT12 by approximately 5 to 6 nmol/L in both sexes (p < 0.01), suggesting a light-dependent modulation of adenosine availability. To further examine the role of adenosine signaling, we performed genetic interference experiments targeting the adenosine receptor. These results indicate that adenosine receptor-associated signaling is functionally involved in the beneficial effects of light, as disruption of this pathway attenuates the light-induced improvements in behavioral and mitochondrial phenotypes. Using a mito-QC reporter system, we further show that light exposure enhances mitochondrial quality control, as reflected by a ~2.3-fold increase in mitolysosome density (p < 0.001). Importantly, this effect is modulated by the functional state of adenosine signaling, suggesting a potential interaction between these processes. Conclusions: Together, our findings indicate that light exposure is associated with coordinated changes in adenosine signaling and mitochondrial quality control, which may contribute to the attenuation of Tau-induced deficits in Drosophila. This work provides insight into how environmental light cues may influence neurodegeneration-related cellular processes and highlights the potential relevance of light-based interventions for future mechanistic and translational studies.