title: Human apolipoprotein E ɛ4 expression impairs cerebral vascularization and blood-brain barrier function in mice.
abstract: Human apolipoprotein E (APOE) exists in three isoforms ɛ2, ɛ3, and ɛ4, of which APOE4 is the main genetic risk factor of Alzheimer's disease (AD). As cerebrovascular defects are associated with AD, we tested whether APOE genotype has an impact on the integrity and function of the blood-brain barrier (BBB) in human APOE-targeted replacement mice. Using the quantitative in situ brain perfusion technique, we first found lower (13.0% and 17.0%) brain transport coefficient (Clup) of [(3)H]-diazepam in APOE4 mice at 4 and 12 months, compared with APOE2 and APOE3 mice, reflecting a decrease in cerebral vascularization. Accordingly, results from immunohistofluorescence experiments revealed a structurally reduced cerebral vascularization (26% and 38%) and thinner basement membranes (30% and 35%) in 12-month-old APOE4 mice compared with APOE2 and APOE3 mice, suggesting vascular atrophy. In addition, APOE4 mice displayed a 29% reduction in [(3)H]-d-glucose transport through the BBB compared with APOE2 mice without significant changes in the expression of its transporter GLUT1 in brain capillaries. However, an increase of 41.3% of receptor for advanced glycation end products (RAGE) was found in brain capillaries of 12-month-old APOE4 mice. In conclusion, profound divergences were observed between APOE genotypes at the cerebrovascular interface, suggesting that APOE4-induced BBB anomalies may contribute to AD development.
authors.affiliation: 1] Faculty of Pharmacy, Université Laval, Québec, QC, Canada [2] Neurosciences Axis, Centre de recherche du CHU de Québec, Québec, QC, Canada.
authors.forename: Wael
authors.initials: W
authors.lastname: Alata
authors.affiliation: 1] Faculty of Pharmacy, Université Laval, Québec, QC, Canada [2] Neurosciences Axis, Centre de recherche du CHU de Québec, Québec, QC, Canada.
authors.forename: Yue
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Neurosciences Axis, Centre de recherche du CHU de Québec, Québec, QC, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: St-Amour
authors.affiliation: 1] Faculty of Pharmacy, Université Laval, Québec, QC, Canada [2] Neurosciences Axis, Centre de recherche du CHU de Québec, Québec, QC, Canada.
authors.forename: Milène
authors.initials: M
authors.lastname: Vandal
authors.affiliation: 1] Faculty of Pharmacy, Université Laval, Québec, QC, Canada [2] Neurosciences Axis, Centre de recherche du CHU de Québec, Québec, QC, Canada.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Calon
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D053329:Apolipoprotein E2 / Q000235:genetics; D053318:Apolipoprotein E3 / Q000235:genetics; D053327:Apolipoprotein E4 / Q000235:genetics*; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000502:physiology*; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000235:genetics*; D003975:Diazepam / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010477:Perfusion; D020033:Protein Isoforms
chemical_list: D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D020033:Protein Isoforms; D003975:Diazepam