EFFECTS OF THE MULTIFACTORIAL CHRONOKINE HEBE2 IN HUMAN IPSC-DERIVED NEURAL CELLS MODELING ALZHEIMER'S DISEASE

Chronokines, and other proteins with age-regulated activity, have emerged as a promising tool to tackle ageing-associated pathologies, as their long-term expression has shown to provide beneficial effects on such disorders without toxicity or adverse side-effects. In this context, and with a focus on a multifactorial disease such as Alzheimer’s Disease (AD), our group has designed and engineered a new chimeric protein named HEBE2, by merging the sTREM2, sKlotho and TIMP2 soluble proteins, with the aim of targeting multiple AD affected pathways simultaneously.
In this study, HEBE2 was functionally characterized in vitro, evaluating whether the activity of each individual subunit is maintained in the chimeric conformation.
Once its functionality was confirmed, the effects of HEBE2 were tested both in vitro, using human iPSC derived microglia cell lines, and in vivo, in a mouse model for AD. The microglial phagocytic capacity as well as the secretion of cytokines was evaluated. In addition, a health span study was conducted, complemented by the chemical composition analysis of AD mice brains through infrared microspectroscopy.
Our main results demonstrate that HEBE2 modulates the activation profile of microglial cells, increasing both the capacity of ApoE4/4 microglia to phagocytose beta-amyloid monomers and their secretion of IL-6, IL12 P70 and IL-1b. Furthermore, HEBE2 also partially restores the altered molecular brain composition in AD animals.
Altogether, this proof of concept lays the foundation for the development of gene therapy strategies using chimeric proteins to address multifactorial pathologies such as Alzheimer’s Disease.