Cracking Amyloid Toxicity: Naringin Rescues Neuronal Cells in a Minimal Alzheimer’s Model

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, extracellular amyloid plaque accumulation, and neuronal dysfunction. The diphenylalanine (Phe-Phe) dipeptide, a core self-assembling motif of amyloid-β (Aβ) peptides, has recently gained attention as a simplified and cost-effective model for mimicking amyloid aggregation <i>in vitro</i>. In this study, we established a Phe-Phe-induced AD model in SH-SY5Y neuroblastoma cells to investigate the effects of naringin (NAR), a <i>Citrus</i>-derived flavanone glycoside known for its antioxidative and anti-inflammatory properties, on AD. Following Phe-Phe exposure, cells were treated with NAR at subcytotoxic concentrations. Multiple end points including cytotoxicity, reactive oxygen species (ROS) generation, DNA damage (Comet assay), AD-related biomarkers (acetylcholinesterase (AChE), amyloid beta (Aβ), amyloid precursor protein (APP), tau protein), cytokine levels, caspase activation, and apoptosis were evaluated. NAR treatment significantly attenuated Phe-Phe-induced ROS production, genotoxicity, and inflammatory responses, while reducing apoptotic cell death and restoring biomarker levels toward physiological norms. These findings demonstrate that NAR exerts multitargeted neuroprotective effects and suggest its therapeutic potential in AD. Additionally, the Phe-Phe model was validated as a reproducible and biologically relevant <i>in vitro</i> system for screening anti-amyloid agents.