C-Terminal Fragment, Aβ(39–42)-Based Tetrapeptides Mitigates Amyloid-β Aggregation-Induced Toxicity

[Image: see text] Since the introduction of acetyl cholinesterase inhibitors as the first approved drugs by the US Food and Drug Administration for Alzheimer’s disease (AD) in clinics, less than satisfactory success in the design of anti-AD agents has impelled the scientists to also focus toward inhibition of Aβ aggregation. Considering the specific binding of fragments for their parent peptide, herein, we synthesized more than 40 new peptides based on a C-terminus tetrapeptide fragment of Aβ(1–42). Initial screening by MTT cell viability assay and supportive results by ThT fluorescence assay led us to identify a tetrapeptide showing complete inhibition for Aβ(1–42) aggregation. Peptide 20 displayed 100% cell viability at 20 μM concentration, while at lower concentrations of 10 and 2 μM 76.6 and 70% of cells were viable. Peptide 20 was found to restrict the conformational transition of Aβ(1–42) peptide toward β-sheet structure. Inhibitory activity of tetrapeptide 20 was further evidenced by the absence of Aβ(1–42) aggregates in electron microscopy. Peptide 20 and other significantly active tetrapeptide analogues could prove imperative in the future design of anti-AD agents.