Selenoprotein P and apolipoprotein E receptor-2 interact at the blood-brain barrier and also within the brain to maintain an essential selenium pool that protects against neurodegeneration.
Selenoprotein P (Sepp1) and its receptor, apolipoprotein E receptor 2 (apoER2), account for brain retaining selenium better than other tissues. The primary sources of Sepp1 in plasma and brain are hepatocytes and astrocytes, respectively. ApoER2 is expressed in varying amounts by tissues; within the brain it is expressed primarily by neurons. Knockout of Sepp1 or apoER2 lowers brain selenium from ∼120 to ∼50 ng/g and leads to severe neurodegeneration and death in mild selenium deficiency. Interactions of Sepp1 and apoER2 that protect against this injury have not been characterized. We studied Sepp1, apoER2, and brain selenium in knockout mice. Immunocytochemistry showed that apoER2 mediates Sepp1 uptake at the blood-brain barrier. When Sepp1(-/-) or apoER2(-/-) mice developed severe neurodegeneration caused by mild selenium deficiency, brain selenium was ∼35 ng/g. In extreme selenium deficiency, however, brain selenium of ∼12 ng/g was tolerated when both Sepp1 and apoER2 were intact in the brain. These findings indicate that tandem Sepp1-apoER2 interactions supply selenium for maintenance of brain neurons. One interaction is at the blood-brain barrier, and the other is within the brain. We postulate that Sepp1 inside the blood-brain barrier is taken up by neurons via apoER2, concentrating brain selenium in them.
Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA raymond.burk@vanderbilt.edu.
Raymond F
RF
Burk
Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Kristina E
KE
Hill
Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Amy K
AK
Motley
Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Virginia P
VP
Winfrey
Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Suguru
S
Kurokawa
Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Stuart L
SL
Mitchell
Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Wanqi
W
Zhang
D000818:Animals; D020296:Animals, Congenic; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D002196:Capillaries / Q000378:metabolism; D002831:Choroid Plexus / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D004705:Endocytosis; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D026502:LDL-Receptor Related Proteins / Q000172:deficiency / Q000502:physiology*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D009474:Neurons / Q000378:metabolism; D011247:Pregnancy; D012643:Selenium / Q000008:administration & dosage / Q000172:deficiency / Q000378:metabolism* / Q000493:pharmacokinetics; D051149:Selenoprotein P / Q000172:deficiency / Q000502:physiology*
D026502:LDL-Receptor Related Proteins; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C055127:Lrp2 protein, mouse; D051149:Selenoprotein P; C098773:low density lipoprotein receptor-related protein 8; D012643:Selenium
choroid plexus; megalin