Deletion of apolipoprotein E receptor-2 in mice lowers brain selenium and causes severe neurological dysfunction and death when a low-selenium diet is fed

Abstract

Selenoprotein P (Sepp1) is a plasma and extracellular protein that is rich in selenium. Deletion of Sepp1 results in sharp decreases of selenium levels in the brain and testis with dysfunction of those organs. Deletion of Sepp1 also causes increased urinary selenium excretion, leading to moderate depletion of whole-body selenium. The lipoprotein receptor apolipoprotein E receptor-2 (apoER2) binds Sepp1 and facilitates its uptake by Sertoli cells, thus providing selenium for spermatogenesis. Experiments were performed to assess the effect of apoER2 on the concentration and function of selenium in the brain and on whole-body selenium. ApoER2-/- and apoER2+/+ male mice were fed a semipurified diet with selenite added as the source of selenium. ApoER2-/- mice had depressed brain and testis selenium, but normal levels in liver, kidney, muscle, and the whole body. Feeding a selenium-deficient diet to apoER2-/- mice led to neurological dysfunction and death, with some of the characteristics exhibited by Sepp1-/- mice fed the same diet. Thus, although it does not affect whole-body selenium, apoER2 is necessary for maintenance of brain selenium and for prevention of neurological dysfunction and death under conditions of selenium deficiency, suggesting an interaction of apoER2 with Sepp1 in the brain.

Figure 1.

Effect of deletion of apoER2 on tissue selenium concentration in mice. The mice were fed a diet supplemented with 0.25 mg of selenium/kg diet for 4 weeks beginning at weaning. The mouse selenium nutritional requirement is 0.1 mg/kg diet. Whole-body selenium was calculated for each mouse by summing the values of each tissue and the residual carcass. Values shown are means and error bars representing 1 SD (n = 5). Asterisks indicate the tissues that were different (p < 0.05) by Student's t test between genotypes.

Figure 2.

Survival of apoER2^−/− male mice (n = 15) fed a selenium-deficient diet beginning at weaning. Wild-type (apoER2^+/+) mice do not develop neurological dysfunction when fed a selenium-deficient diet and do not have shortened survival.