AbstractAimsWe previously found that a decoy peptide derived from the C‐terminal sequence of α‐Synuclein (αSyn) prevents cytotoxic αSyn aggregation caused by fatty acid‐binding protein 3 (FABP3) in vitro. In this study, we continued to utilize αSyn‐derived peptides to further validate their effects on αSyn neurotoxicity and behavioral impairments in αSyn preformed fibrils (PFFs)‐injected mouse model of Parkinson's disease (PD).MethodsMice were injected with αSyn PFFs in the bilateral olfactory bulb (OB) and then were subjected to behavioral analysis at 2‐week intervals post‐injection. Peptides nasal administration was initiated one week after injection. Changes in phosphorylation of αSyn and neuronal damage in the OB were measured using immunostaining at week 4. The effect of peptides on the interaction between αSyn and FABP3 was examined using co‐immunoprecipitation.ResultsαSyn PFF‐injected mice showed significant memory loss but no motor function impairment. Long‐term nasal treatment with peptides effectively prevented memory impairment. In peptide‐treated αSyn PFF‐injected mice, the peptides entered the OB smoothly through the nasal cavity and were mainly concentrated in neurons in the mitral cell layer, significantly suppressing the excessive phosphorylation of αSyn and reducing the formation of αSyn‐FABP3 oligomers, thereby preventing neuronal death. The addition of peptides also blocked the interaction of αSyn and FABP3 at the recombinant protein level, and its effect was strongest at molar concentrations comparable to those of αSyn and FABP3.ConclusionsOur findings suggest that the αSyn decoy peptide represents a novel therapeutic approach for reducing the accumulation of toxic αSyn‐FABP3 oligomers in the brain, thereby preventing the progression of synucleinopathies.