Glial Progenitor Cell Therapy Improves Mitochondrial Function in the Hippocampus of 5xFAD Mice, but Does Not Restore the Multiscale Structure of Behavioral Stress Response

Cell therapy is increasingly used to treat a variety of medical conditions, including cancer, immune system disorders, and neurodegeneration. Stem cells secrete growth factors, signaling molecules, and extracellular vesicles, that can be used to treat neurological diseases and promote neuronal regeneration. Transgenic 5xFAD mice, which are a model for Alzheimer’s disease (AD), were used in this study. The mice were 7 months old and received retro-orbital injections of glial progenitor cells (GPCs) once a week for 4 months. At 11 months, their behavior was analyzed using a multichannel actigraphy system. Brain tissues from the cortex, hippocampus, and midbrain were collected for postmortem analysis of mitochondrial respiratory chain enzyme activity. The results showed that the GPCs injection significantly improved the response of the hippocampal p2 mitochondrial fraction in 5xFAD mice to succinate, reaching a level observed in control animals. A similar trend was also observed for the cytochrome c oxidase complex. The oxygen consumption rate of mitochondria did not differ from that of clinically healthy mice after ascorbate/N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride administration. A similar decrease in the efficiency of the electron transport chain was detected in the midbrain of 5xFAD mice, but no recovery was observed after GPCs treatment. Behavioral differences between non‑transgenic and transgenic groups were observed in a multiparameter analysis using the actigraphy system. The behavior of transgenic mice in the treated and untreated groups was similar, while the behavior of non-transgenic mice varied. Additional analysis of locomotor activity and transient events in particular revealed that the activity of the GPCs-treated 5xFAD mice was differed fundamentally compared to other groups. Specifically, GPCs-treated mice exhibited greater number of transitions between intermediate activity states. In contrast, untreated mice showed transitions between extreme activity states, such as from low to high activity or vice versa. These findings suggest that changes in behavior and activity of the AD mice may be associated not only with hippocampal dysfunction, but also with disruptions in midbrain structures.