P1642-1, a novel pancreatic polypeptide analogue, ameliorates cognitive impairment in 5 ×FAD mice and is associated with enhanced PINK1/Parkin-related mitophagy.

Currently, few pharmacological treatments are available for Alzheimer's disease (AD). However, gut-brain peptides, especially pancreatic polypeptide (PP) analogues, have shown promise. PP analogues have been reported to cross the blood-brain barrier and activate neuropeptide Y4 receptor (NPY4R) in the brain, thereby ameliorating AD-related cognitive deficits. P1642-1 is a novel PP analogue, but its role and mechanism in AD remain unexplored. This study utilized 5 ×FAD mice as a model to assess the effects of P1642-1 on cognitive dysfunction and its underlying mechanisms, while an Aβ25-35-induced cellular model was used to provide complementary mechanistic support. The findings revealed that administration of P1642-1 significantly ameliorated cognitive deficits, alleviated neuronal injury, decreased β-amyloid (Aβ) accumulation, and attenuated mitochondrial damage in the hippocampus of 5 ×FAD mice. These improvements were accompanied by enhanced mitophagy, as evidenced by upregulation of the PINK1/Parkin axis, increased LC3-II, and decreased p62 levels. In the Aβ25-35-induced cellular AD model, P1642-1 also exerted neuroprotective effects and was associated with the regulation of PINK1/Parkin-related mitophagy. Molecular dynamics simulation suggested that P1642-1 may interact with NPY4R, although receptor expression in hippocampal neurons was not directly verified in the present study. In conclusion, our study suggests that the novel PP analogue P1642-1 ameliorates cognitive impairment in 5 ×FAD mice and is associated with enhanced PINK1/Parkin-related mitophagy. These findings provide experimental support for further investigation of P1642-1 as a potential therapeutic candidate for AD.