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 Ϫ/Ϫ and apoER2 ϩ/ϩ male mice were fed a semipurified diet with selenite added as the source of selenium. ApoER2 Ϫ/Ϫ 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 Ϫ/Ϫ mice led to neurological dysfunction and death, with some of the characteristics exhibited by Sepp1 Ϫ/Ϫ 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.

Selenoproteins: Molecular Pathways and Physiological Roles

“…ApoER2 was shown to bind SelP and facilitate its uptake by testis and brain (35,276). Consistent with its role in Se metabolism in these tissues, ApoER2 knockout mice showed sharply decreased Se levels in testis and brain that were associated with neurological dysfunction and defective spermatogenesis similar to phenotypes observed in SelP Ϫ/Ϫ mice.…”

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

“…Apoer2 also protects against neurodegeneration through another, mechanistically distinct mechanism, which involves its role in the uptake of essential selenoproteins into the brain (Burk et al 2007). Loss of Apoer2 sensitizes the animals to low dietary selenium levels resulting in death from rapid and severe neurodegeneration.…”

Molecular biology of glutathione peroxidase 4: from genomic structure to developmental expression and neural function

“…At the time of writing, a study by Burk et al (2007) was published that reports on slightly lower brain selenium levels in apoER2 knockout mice. Although the question as to whether apoER2 regulates GPx4 expression is still unanswered, these recent data suggest that the apoER2 -/-phenotype may also be attributed to overall altered selenoprotein expression in neurons and glial cells.…”