-Synuclein decoy peptide protects mice against -synuclein-induced memory loss

Aims: We previously found that a decoy peptide derived from the C-terminal sequence of alpha- Synuclein (alpha Syn) prevents cytotoxic alpha Syn aggregation caused by fatty acid-binding protein 3 (FABP3) in vitro. In this study, we continued to utilize alpha Syn-derived peptides to further validate their effects on alpha Syn neurotoxicity and behavioral impairments in alpha Syn preformed fibrils (PFFs)-injected mouse model of Parkinson's disease (PD).Methods: Mice were injected with alpha Syn 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 alpha Syn and neuronal damage in the OB were measured using immunostaining at week 4. The effect of peptides on the interaction between alpha Syn and FABP3 was examined using co-immunoprecipitation. Results: alpha Syn 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 alpha Syn 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 alpha Syn and reducing the formation of alpha Syn- FABP3 oligomers, thereby preventing neuronal death. The addition of peptides also blocked the interaction of alpha Syn and FABP3 at the recombinant protein level, and its effect was strongest at molar concentrations comparable to those of alpha Syn and FABP3.Conclusions: Our findings suggest that the alpha Syn decoy peptide represents a novel therapeutic approach for reducing the accumulation of toxic alpha Syn- FABP3 oligomers in the brain, thereby preventing the progression of synucleinopathies.