The Sex-Dependent Effects of Psychedelics on Myelination in APOE4 Mice

Abstract: Several studies have linked myelin abnormalities with neuropsychiatric disorders; others have implicated psychedelics as a potential therapeutic for such conditions. One risk factor for these demyelinating disorders is a mutation in the Apolipoprotein E gene known as APOE4. This variant impedes the cholesterol regulation of oligodendrocytes responsible for the myelination, or insulation, of neurons when compared to the wild-type phenotype. In this work, I advance knowledge of cellular pathways involved in the progression of APOE4-related diseases and elucidate the effects of psychedelics on the brain. Myelin sheaths are vital for maintaining neural pathways, and healthy oligodendrocytes serve as a prerequisite for axonal integrity. Further, the Kaufer Lab has observed significant behavioral differences between male and female APOE4 mice following psychedelic treatment with 2,5-Dimethoxy-4-iodoamphetamine, or DOI, a serotonin receptor ligand. The sex-dependent mechanisms influencing symptom differences and treatment outcomes in AD are unclear, and could be key to developing successful therapeutics for myelin-related issues. I hypothesize that administration of DOI will increase the myelination activity of oligodendrocytes in female APOE4 mice compared with their male counterparts or controls. Preliminary results show a significant increase in MBP in the CA1, or short-term, and CA2, or long term, areas in only female APOE4 mice post-introduction of DOI to the system. This aligns with behavioral data indicating fewer anxiety-related behaviors in female APOE4 mice after DOI administration. These findings reveal distinct biological mechanisms in male and female brain degeneration and suggest potential for sex-specific therapeutics.