title: Evidence for synergistic action of transthyretin and IGF-I over the IGF-I receptor.
abstract: Transthyretin (TTR) has a neuroprotective role in the central nervous system (CNS) in Alzheimer's disease (AD) and cerebral ischemia. Increased levels of TTR and activated insulin-like growth factor I receptor (IGF-IR) are associated with reduced neurodegeneration in an AD mouse model. In the present study, we found that TTR and IGF-I have a synergistic effect on activation of one of the IGF-IR signaling pathways. Hippocampus of TTR null mice present decreased levels of phosphorylated IGF-IR and Akt when compared with TTR wild type littermate animals. Cell studies reveal the synergistic effect of TTR and IGF-I in promoting IGF-IR signaling even under glutamate induced toxicity. TTR:IGF-IR complexes are identified and a bio-layer interferometry assay demonstrated an interaction between TTR and IGF-IR with a KD ranging from 99 to 744nM. In summary, our results point to a new TTR role through the IGF-I axis, mediated through TTR-IGF-IR interactions.
authors.affiliation: I3S - Instituto de Investigação e Inovação em Saúde, Unidade de Neurobiologia Molecular, IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
authors.forename: Marta
authors.initials: M
authors.lastname: Vieira
authors.affiliation: Instituto Tecnologia Química e Biológica, Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal.
authors.forename: Sónia S
authors.initials: SS
authors.lastname: Leal
authors.affiliation: Instituto Tecnologia Química e Biológica, Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal.
authors.forename: Cláudio M
authors.initials: CM
authors.lastname: Gomes
authors.affiliation: I3S - Instituto de Investigação e Inovação em Saúde, Unidade de Neurobiologia Molecular, IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal. Electronic address: mjsaraiv@ibmc.up.pt.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Saraiva
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D011228:Prealbumin; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt
keywords: Glutamate; Ischemia; Protein–protein interaction; Synergy