P1642-1, a novel pancreatic polypeptide analogue, ameliorates cognitive impairment in 5×FAD mice by enhancing PINK1/Parkin mitophagy.

Current pharmacological treatments for Alzheimer's disease (AD) are limited, highlighting an urgent need for novel therapeutic strategies. Gut-brain peptides, particularly pancreatic polypeptide (PP) analogues, show promise due to their ability to cross the blood-brain barrier and activate the neuropeptide Y4 receptor (NPY4R) in the brain. This mechanism has been implicated in ameliorating AD-related cognitive deficits. P1642-1 is a new PP analogue whose specific role and mechanism in AD had not been previously investigated.

This study evaluated the effects of P1642-1 in a 5×FAD mouse model of Alzheimer's disease to assess cognitive dysfunction and its underlying mechanisms. An Aβ25-35-induced cellular model was also utilized to provide complementary mechanistic insights. The researchers administered P1642-1 (dose not specified in abstract) and measured primary endpoints including cognitive deficits, neuronal injury, β-amyloid (Aβ) accumulation, and mitochondrial damage in the hippocampus. Mitophagy markers like PINK1/Parkin axis proteins, LC3-II, and p62 levels were also assessed. Molecular dynamics simulations were used to predict NPY4R interaction.