title: Transthyretin participates in beta-amyloid transport from the brain to the liver--involvement of the low-density lipoprotein receptor-related protein 1?
abstract: Transthyretin (TTR) binds Aβ peptide, preventing its deposition and toxicity. TTR is decreased in Alzheimer's disease (AD) patients. Additionally, AD transgenic mice with only one copy of the TTR gene show increased brain and plasma Aβ levels when compared to AD mice with both copies of the gene, suggesting TTR involvement in brain Aβ efflux and/or peripheral clearance. Here we showed that TTR promotes Aβ internalization and efflux in a human cerebral microvascular endothelial cell line, hCMEC/D3. TTR also stimulated brain-to-blood but not blood-to-brain Aβ permeability in hCMEC/D3, suggesting that TTR interacts directly with Aβ at the blood-brain-barrier. We also observed that TTR crosses the monolayer of cells only in the brain-to-blood direction, as confirmed by in vivo studies, suggesting that TTR can transport Aβ from, but not into the brain. Furthermore, TTR increased Aβ internalization by SAHep cells and by primary hepatocytes from TTR+/+ mice when compared to TTR-/- animals. We propose that TTR-mediated Aβ clearance is through LRP1, as lower receptor expression was found in brains and livers of TTR-/- mice and in cells incubated without TTR. Our results suggest that TTR acts as a carrier of Aβ at the blood-brain-barrier and liver, using LRP1.
authors.affiliation: IBMC-Instituto de Biologia Molecular e Celular.|i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.|Faculdade de Medicina, Universidade do Porto, Porto, Portugal.
authors.forename: Mobina
authors.initials: M
authors.lastname: Alemi
authors.affiliation: IBMC-Instituto de Biologia Molecular e Celular.|i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Gaiteiro
authors.affiliation: IBMC-Instituto de Biologia Molecular e Celular.|i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.
authors.forename: Carlos Alexandre
authors.initials: CA
authors.lastname: Ribeiro
authors.affiliation: IBMC-Instituto de Biologia Molecular e Celular.|i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.
authors.forename: Luís Miguel
authors.initials: LM
authors.lastname: Santos
authors.affiliation: IBMC-Instituto de Biologia Molecular e Celular.|i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.
authors.forename: João Rodrigues
authors.initials: JR
authors.lastname: Gomes
authors.affiliation: IBMC-Instituto de Biologia Molecular e Celular.|i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.|Faculdade de Medicina, Universidade do Porto, Porto, Portugal.
authors.forename: Sandra Marisa
authors.initials: SM
authors.lastname: Oliveira
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Couraud
authors.affiliation: Weill Cornell Medical College, Division of Hematology-Medical Oncology, 1300 York Avenue Rm C 606, New York, NY 10065.
authors.forename: Babette
authors.initials: B
authors.lastname: Weksler
authors.affiliation: Department of Life, Health and Chemical Sciences, Open University, Milton Keynes, U.K.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Romero
authors.affiliation: IBMC-Instituto de Biologia Molecular e Celular.|i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Saraiva
authors.affiliation: IBMC-Instituto de Biologia Molecular e Celular.|i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Cardoso
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D008099:Liver / Q000378:metabolism*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011228:Prealbumin / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport
chemical_list: D016229:Amyloid beta-Peptides; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011228:Prealbumin
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