HEBE: A novel chimeric chronokine for ameliorating memory deficits in Alzheimer's disease

Abstract

Alzheimer’s disease; Chimeric protein; Memory impairment

Enfermedad de Alzheimer; Proteína quimérica; Deterioro de memoria

Malaltia d'Alzheimer; Proteïna quimèrica; Deteriorament de la memòria

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder characterized by amyloid-β and Tau protein depositions, with treatments focusing on single proteins have shown limited success due to the complexity of pathways involved. This study explored the potential of chronokines —proteins that modulate aging-related processes— as an alternative therapeutic approach. Specifically, we focused on a novel pleiotropic chimeric protein named HEBE, combining s-KL, sTREM2 and TIMP2, guided by bioinformatic analyses to ensure the preservation of each protein’s conformation, crucial for their functions. In vitro studies confirmed HEBE’s stability and enzymatic activities, even suggesting it has different activities compared to the individual chronokines. In vivo experiments on APP/Tau mice revealed improved learning and memory functions with HEBE treatment, along with decreased levels of phosphorylated Tau and minor effects on amyloid-β levels. These findings suggest that HEBE is as a promising therapeutic candidate for ameliorating memory deficits and reducing pTau in an AD mouse model.

This work was funded by MICINN/AEI/10.13039/501100011033 (PID2022–142624OB-I00 and PID2019–104034RB-I00 to MC); (PID2022-137668OB-I00) to CS; and (PID2023–148834OB-I00) to AB; by Instituto de Salud Carlos III and NexGenerationEU (RICORS, RD21/0017/0008) to MC and AB; and Generalitat de Catalunya (2021SGR-00529) to AB and MC, and (2021SGR-00142) to CS. JE was a recipient of a fellowship by the Generalitat de Catalunya (2020FI-SDUR0037). DRG was a recipient of a VHIR Fellowship. RB was a recipient of a fellowship by the Gobierno de España (FPU16/03137). MDCL was a recipient of a fellowship by the Ministerio de Ciencia e Innovación (BES-2017-082072).