title: Apolipoprotein E regulates the integrity of tight junctions in an isoform-dependent manner in an in vitro blood-brain barrier model.
abstract: Apolipoprotein E (apoE) is a major apolipoprotein in the brain. The ε4 allele of apoE is a major risk factor for Alzheimer disease, and apoE deficiency in mice leads to blood-brain barrier (BBB) leakage. However, the effect of apoE isoforms on BBB properties are as yet unknown. Here, using an in vitro BBB model consisting of brain endothelial cells and pericytes prepared from wild-type (WT) mice, and primary astrocytes prepared from human apoE3- and apoE4-knock-in mice, we show that the barrier function of tight junctions (TJs) was impaired when the BBB was reconstituted with primary astrocytes from apoE4-knock-in mice (apoE4-BBB model). The phosphorylation of occludin at Thr residues and the activation of protein kinase C (PKC)η in mBECs were attenuated in the apoE4-BBB model compared with those in the apoE3-BBB model. The differential effects of apoE isoforms on the activation of PKCη, the phosphorylation of occludin at Thr residues, and TJ integrity were abolished following the treatment with an anti-low density lipoprotein receptor-related protein 1 (LRP1) antibody or a LRP1 antagonist receptor-associated protein. Consistent with the results of in vitro studies, BBB permeability was higher in apoE4-knock-in mice than in apoE3-knock-in mice. Our studies provide evidence that TJ integrity in BBB is regulated by apoE in an isoform-dependent manner.
authors.affiliation: Department of Alzheimer's Disease Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8522, Japan.
authors.forename: Kazuchika
authors.initials: K
authors.lastname: Nishitsuji
authors.forename: Takashi
authors.initials: T
authors.lastname: Hosono
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Nakamura
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.forename: Makoto
authors.initials: M
authors.lastname: Michikawa
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D053318:Apolipoprotein E3 / Q000235:genetics / Q000378:metabolism*; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000235:genetics; D055879:Gene Knock-In Techniques; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D062793:Occludin; D020286:Pericytes / Q000378:metabolism* / Q000473:pathology; D010539:Permeability; D010766:Phosphorylation / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D020033:Protein Isoforms; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; C119190:protein kinase C nu; D011493:Protein Kinase C