Structural Conversion\nof Serotonin into Amyloid-like\nNanoassemblies Conceptualizes an Unexplored Neurotoxicity Risk

The neuromodulator 5-hydroxytryptamine, known as serotonin,\nplays\na key regulatory role in the central nervous system and peripheral\norgans; however, several research revelations have indicated a direct\nlink between the oxidation of serotonin and a plethora of detrimental\nconsequences. Hence, the question of how several neuronal and non-neuronal\ncomplications originate via serotonin oxidation remains an important\narea of investigation. Here, we show the autoxidation-driven structural\nconversion of serotonin into hemolytic and cytotoxic amyloid-like\nnanoassemblies under physiological conditions. We also observed the\ncatalysis of serotonin oxidation in the presence of Aβ<sub>1–42</sub> amyloid fibrils and Cu(II) ions. The serotonin nanostructures generated\nfrom its spontaneous and amyloid-mediated oxidation exhibited typical\nstructural and functional characteristics of amyloid entities, and\ntheir effective internalization in neuroblastoma cells caused cell-damaging\neffects via cytosolic aggregation, ROS generation and necrosis/apoptosis-mediated\ncell death. Since imbalance in the serotonin level is known to predispose\ndiverse pathological conditions including serotonin syndrome, atherosclerosis,\ndiabetes, and Alzheimer’s diseases, our results on the formation\nof cytotoxic nanoassemblies via serotonin oxidation may provide important\nevidence for understanding the molecular mechanism of serotonin associated\ncomplications.