Selenoprotein P and apolipoprotein E receptor‐2 interact at the blood‐brain barrier and within the brain to protect against neurodegeneration (374.6)

Abstract

The brain retains selenium under selenium‐deficient (0 Se) conditions better than other tissues. Selenoprotein P (Sepp1) and its receptor apolipoprotein E receptor‐2 (apoER2) are both necessary for this retention. Feeding 0 Se diet to weanling mice with either of these proteins knocked out leads to severe brain injury within 4 weeks. Little is known about the interactions of Sepp1 and apoER2 that protect against brain injury. We studied these proteins and brain selenium in knockout mice. Immunocytochemistry showed that apoER2 mediated Sepp1 uptake by choroid plexus and brain capillaries in the fetus but only by choroid plexus in the adult. ApoER2 mRNA in adult brain was 11% of that in fetal brain, consistent with lesser uptake of Sepp1 at the blood‐brain barrier (BBB) in the adult than in the fetus. Severe brain injury occurred in knockout mice fed 0 Se diet when brain selenium fell to 34‐39 ng/g. However, mice with selective knockout of Sepp1 in hepatocytes fed 0 Se diet for 40 weeks tolerated brain selenium of 12 ng/g without severe brain injury. Thus, Sepp1 within the brain prevents the injury. These results indicate that 2 levels of Sepp1‐apoER2 interaction occur to supply neurons with selenium. One results in selenium uptake at the BBB and the other occurs within the brain. We postulate that Sepp1 synthesized inside the BBB is taken up by neurons through apoER2‐mediated endocytosis, concentrating brain selenium in neurons.Grant Funding Source: Supported by NIH ES002497