Work

A calmodulin-derived peptide TI-16 inhibits Alzheimer's disease progression by decreasing Aβ burden and restoring calcium dyshomeostasis

Year: 2025

Type: article

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive and behavioral impairments. Despite extensive research into the pathogenesis of AD, there is still a lack of effective clinical treatments drugs . In this study, we identified calmodulin (CaM) as a key molecule in the pathological process of AD through bioinformatics analysis and innovatively designed a peptide, TI-16, based on the binding specificity between CaM and amyloid-β (Aβ). We evaluated the improvement effect of TI-16 on the activity and apoptosis of Aβ 25–35 -induced SHSY5Y cells damage by Cell Counting Kit 8 (CCK-8) and Flow cytometry. MOE molecular docking and GST pull-down experiments demonstrated that TI-16 possesses binding affinity for Aβ, and Immunofluorescence staining and Ca 2+ concentration determination experiments showed that TI-16 reduced the co-localization of Aβ and CaM, and could inhibit intracellular calcium overload. Subsequently, Morris water maze tests were conducted to assess the impact of TI-16 on learning and memory abilities in AD model mice. Furthermore, HE staining, Th S staining, and Western blot analysis were utilized to investigate the improvement effect of TI-16 on the pathological damage of AD. The results indicate that TI-16 can target Aβ to increase the intracellular free concentration of CaM, and effectively regulate intracellular Ca 2+ homeostasis . Notably, TI-16 significantly enhanced cognitive function in AD model mice, reduced Aβ deposition, alleviated neuronal damage, inhibited neuronal apoptosis , and thereby improved AD progression . As a potentially effective peptide therapeutic drug for AD, TI-16 offers a novel target and introduces a fresh perspective for future clinical applications.

Source: Bioorganic Chemistry

DOI: 10.1016/j.bioorg.2025.108502