Impact of Aging and Sex on the Expression and Function of Xenobiotic Transporters at the Blood-CSF Barrier

Abstract ID 91926 Poster Board 427 The blood-cerebrospinal fluid barrier (BCSFB), formed by the choroid plexuses (CP) in the ventricles, serves as a critical clearance organ in the brain by mediating bulk-flow CSF clearance and through the active removal of drugs and metabolites by transporters. The CP epithelial cells are understood to go through morphological and functional changes during aging, leading to a reduction in CSF secretion rate. Emerging evidence also indicate that drug transporter expression can exhibit sex differences in drug disposition organs such as the liver, potentially contributing to differences in drug response. Currently little is known regarding the impact of aging and sex on transporter expression and function at the BCSFB. The primary objective of this study is to determine if mRNA expression of major xenobiotic transporters at the BCSFB is dependent on aging and sex using a rodent model. A secondary objective is to examine if aging and sex alters BCSFB transporter function in live tissue, employing a quantitative real-time imaging method recently developed in our laboratory. CP tissues were harvested from young adult (3 months) and old (20 months) mouse brains. The mRNA expression of Slc transporters (Slc22a6, Slc22a8, Slc15a2, Slc29a4, Slco1a1, Slco1a4, Slco1a5, Slco1a6, Slco1c1, Slco3a1) and Abc transporters (Abcb1a, Abcb1b, Abcg2, Abcc1, Abcc4) were analyzed by RT-qPCR. Aquaporin 1 (Aqp1) was used as a marker for CP epithelial cells, and Gapdh and GusB were used as the housekeeping genes. The results showed that while the majority of analyzed genes showed no difference in expression between the two age groups, Abcg2 (Bcrp) mRNA levels increased in aged mice by 70% and 100% in male and female CP tissues, respectively. In contrast, the expression of Slco3a1 (Oatp3a1) was decreased in aged mice by 30% in males and 40% in females. In young adult mice, no significant sex differences were observed for all analyzed transporter genes. However, in old mice, Slc22a8 (Oat3) CP expression in females was 40% lower compared to the male cohort. Currently, studies are ongoing to determine whether transporter activity is influenced by aging using quantitative real-time imaging of fluorescent transporter substrates. As BCSFB transporters play a crucial role in removing drugs, toxins, and metabolic wastes from the brain, quantifying the effect of aging and sex on transporter expression and activity at the BCSFB will help to understand how brain concentrations and the pharmacokinetics of CNS-targeted drugs may be affected by sex and in geriatric patients. This study is supported by National Institutes of Health Grant AG071827.