Sucralose Induces Neurobehavioral Alterations and Exacerbates Alzheimer's Disease-Like Phenotypes in Zebrafish Models

Artificial sweeteners are widely consumed, yet their potential neurotoxic effects remain poorly understood. Using sucralose (SUC) as a model compound, this study develops an approach to rapidly screen the neurotoxicity of artificial sweeteners and explore their potential associations with neurodegenerative-like processes, especially Alzheimer's disease (AD)-like phenotypes. SUC is minimally absorbed and metabolized by mammals, leading to its widespread presence in the environment. Here, we integrate high-throughput behavioral phenotyping in larval zebrafish with targeted analyses in adult and AD transgenic models, employing a "behavioral phenoblast" strategy adapted from prior large-scale sleep-wake drug screens. SUC effects were evaluated across a broad concentration range (5 μg/L to 100 mg/L), covering low-dose to high-dose exposure conditions. Hierarchical and K-means clustering revealed that SUC's behavioral signatures closely resembled those of compounds associated with neurodegenerative risks. To validate these findings, adult zebrafish were exposed to SUC within the Acceptable Daily Intake (ADI) range (1-100 mg/L) for 3 months, resulting in dose-dependent increases in anxiety-like behaviors and impairments in learning and memory. Notably, treatment of transgenic zebrafish expressing human misfolded Aβ protein with SUC exacerbated Aβ-related pathological phenotypes in a dose-dependent manner. These findings highlight the need for further investigation into the long-term neurological impacts of artificial sweeteners and provide a methodological framework for evaluating the potential health risks of artificial sweeteners.