title: Transthyretin Induces Insulin-like Growth Factor I Nuclear Translocation Regulating Its Levels in the Hippocampus.
abstract: Transthyretin (TTR) is the carrier protein of thyroxine (T4) and binds to retinol-binding protein (RBP)-retinol complex. It is mainly synthesized by both liver and choroid plexuses of the brain. Besides these properties, it has a neuroprotective role in several contexts such as Alzheimer's disease (AD) and cerebral ischemia. Activation of insulin-like growth factor receptor I (IGF-IR) pathways and increased levels of TTR are associated with absence of neurodegeneration in an AD mouse model. In the present study, we verified that young/adult TTR null mice had decreased levels of IGF-IR in the hippocampus, but not in choroid plexus when compared with wild-type age-matched controls. Moreover, we could also demonstrate that conditional silencing of peripheral TTR did not have any influence in hippocampal IGF-IR levels, indicating that TTR effect on IGF-IR levels is due to TTR mainly synthesized in the choroid plexus. In vitro cellular studies, using NIH3T3 cell line and primary cultured hippocampal neurons, we showed that TTR upregulates IGF-IR at the transcription and translation levels and that is dependent on receptor internalization. Using a GFP-IGF-IR fusion protein, we also found that TTR triggers IGF-IR nuclear translocation in cultured neurons. We could also see an enrichment of IGF-IR in the nuclear fraction, after TTR stimulation in NIH3T3 cells, indicating that IGF-IR regulation, triggered by TTR is induced by nuclear translocation. In summary, the results provide evidence of a new role of TTR as a transcription inducer of IGF-IR in central nervous system (CNS), unveiling a new role in neuroprotection.
authors.affiliation: Molecular Neurobiology Unit, IBMC - Instituto de Biologia Molecular e Celular, Rua do Campo Alegre 823, 4150-180, Porto, Portugal.
authors.forename: Marta
authors.initials: M
authors.lastname: Vieira
authors.forename: João R
authors.initials: JR
authors.lastname: Gomes
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Saraiva
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D006624:Hippocampus / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D009474:Neurons / Q000378:metabolism*; D011228:Prealbumin / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*
chemical_list: D011228:Prealbumin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1
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