A modified form of the peptide humanin (called S14G‑humanin or HNG) helped Alzheimer‑model mice think better by fixing brain insulin signaling and boosting the cell’s cleanup system, which also lowered harmful amyloid plaques. The study was done in mice, not people, so it shows promise but isn’t a ready‑to‑use protocol for humans.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by Aβ plaque deposition in the brain, which is related to the disorder of autophagosome maturation, transport, and formation of autolysosome. Notably, abnormal insulin signaling is connected with cognitive dysfunction in AD. In this study, using APP/PS1 transgenic mice as AD model, we investigated the mechanism by which S14G-humanin (HNG) improved autophagy and insulin signaling in AD brain. Immunohistochemistry was used to determine the levels of mTOR and Aβ deposition, and Western blot analysis was used to determine IRS-1, IRS-1 pSEr636, ULK1, p62, LC3 I/LC3 II protein levels. Our results demonstrated that HNG could improve the learning ability and memory in APP/PS1 transgenic mice, possibly through decreasing IRS-1 Ser636 phosphorylation and mTOR protein expression in the hippocampus, thus improving insulin resistance in the brain. In addition, HNG increased ULK1 expression, decreased p62 and LC3 I/LC3 II protein levels, thus enhancing autophagy and decreasing Aβ deposition in the brain. Taken together, our results suggest that through the regulation of IRS-1/mTOR insulin signaling in the hippocampus, HNG increases the activity of autophagy and decreases Aβ deposition in the brain, and improves learning ability and memory of AD mice.