Melanin Suppresses Aβ Aggregation and Toxicity

The aggregation of amyloid-β (Aβ) peptides into insoluble deposits is a characteristic hallmark of Alzheimer’s disease (AD) and related neurodegenerative disorders. While AD is the most common cause of dementia, there are currently no disease-modifying treatments which are both affordable and adverse-free. In this study, we report that melanin, a pigment which is commonly found in nature and is abundant in parts of the human brain, suppresses the aggregation of the 42-amino acid Aβ variant (Aβ42). Using biophysical and biochemical techniques, we show that melanin delays Aβ42 aggregation while also reducing the amount of Aβ42 that converts into aggregates. Using thioflavin T assays paired with chemical kinetics, we characterised the melanin-induced inhibition of Aβ42 aggregation in vitro. Using MALDI-MS, we elucidate the molecular basis of this effect by showing that melanin prevents Aβ42 dimerisation. We then demonstrate that melanin also reverts the aggregation process by dissolving pre-formed Aβ42 fibrils. Finally, we show that melanin reduces Aβ42 aggregation and rescues Aβ42 toxicity in an SH-SY5Y neuroblastoma cell model. Our study shows that melanin disrupts the aggregation and cytotoxicity of Aβ42, and suggests that compounds derived from human metabolites may offer promising avenues to combat amyloid formation.