Photo-inhibition of Aβ fibrillation mediated by a newly designed fluorinated oxadiazole

Uncontrolled aggregation of amyloid beta peptide (Aβ) is the main cause of Alzheimer's disease. Therapeutic approaches to intervention in amyloid diseases include the use of small molecules able to stabilize the soluble Aβ conformation, or to redirect the amyloidogenic pathway towards non-toxic and non-fibrillar states. Fluorometric measurements revealed that 3-(4′-trifluoromethylphenyl)-5-(4′-methoxyphenyl)-1,2,4-oxadiazole, when irradiated, is able to interact with the monomeric Aβ peptide readdressing the aggregation pathway toward the formation of amorphous aggregates as evidenced by CD, AFM, and SAXS measurements. We hypothesize that this compound, under radiation, forms a reactive intermediate that sticks on the Aβ peptide by interfering with its fibrillation process. Cytotoxicity assays performed on LAN5 neuroblastoma cells suggest that the presence of oxadiazole reduces the toxicity of Aβ. This finding might be the start of innovative therapies against Alzheimer's disease. The interaction of oxadiazole 3 photo-stimulated with Aβ 1-40 induces a structural modification responsible for fibrillogenesis inhibition.