title: Mixed oligomers and monomeric amyloid-β disrupts endothelial cells integrity and reduces monomeric amyloid-β transport across hCMEC/D3 cell line as an in vitro blood-brain barrier model.
abstract: Senile amyloid plaques are one of the diagnostic hallmarks of Alzheimer's disease (AD). However, the severity of clinical symptoms of AD is weakly correlated with the plaque load. AD symptoms severity is reported to be more strongly correlated with the level of soluble amyloid-β (Aβ) assemblies. Formation of soluble Aβ assemblies is stimulated by monomeric Aβ accumulation in the brain, which has been related to its faulty cerebral clearance. Studies tend to focus on the neurotoxicity of specific Aβ species. There are relatively few studies investigating toxic effects of Aβ on the endothelial cells of the blood-brain barrier (BBB). We hypothesized that a soluble Aβ pool more closely resembling the in vivo situation composed of a mixture of Aβ40 monomer and Aβ42 oligomer would exert higher toxicity against hCMEC/D3 cells as an in vitro BBB model than either component alone. We observed that, in addition to a disruptive effect on the endothelial cells integrity due to enhancement of the paracellular permeability of the hCMEC/D3 monolayer, the Aβ mixture significantly decreased monomeric Aβ transport across the cell culture model. Consistent with its effect on Aβ transport, Aβ mixture treatment for 24h resulted in LRP1 down-regulation and RAGE up-regulation in hCMEC/D3 cells. The individual Aβ species separately failed to alter Aβ clearance or the cell-based BBB model integrity. Our study offers, for the first time, evidence that a mixture of soluble Aβ species, at nanomolar concentrations, disrupts endothelial cells integrity and its own transport across an in vitro model of the BBB.
authors.affiliation: Department of Basic Pharmaceutical Science, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA.
authors.forename: Hisham
authors.initials: H
authors.lastname: Qosa
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
authors.forename: Harry
authors.initials: H
authors.lastname: LeVine
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Keller
authors.affiliation: Department of Basic Pharmaceutical Science, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA. Electronic address: kaddoumi@ulm.edu.
authors.forename: Amal
authors.initials: A
authors.lastname: Kaddoumi
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000494:pharmacology*; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D019281:Dimerization; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D055806:Microvessels / Q000378:metabolism / Q000473:pathology*; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D016229:Amyloid beta-Peptides; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic
keywords: Alzheimer's disease; Amyloid-β; Blood–brain barrier; Clearance