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.

Integrated Hypothalamic Transcriptome Profiling Reveals the Reproductive Roles of mRNAs and miRNAs in Sheep

“…The expression level of TTR's in rats could be enhanced by progesterone via progesterone receptors both in vitro and in vivo (Quintela et al, 2011), and a similar upregulated effect of TTR caused by progesterone in mouse uterus was also observed (Diao et al, 2010). Furthermore, TTR could drive the nuclear translocation of insulin-like growth factor 1 receptor (IGF-1R) (Vieira et al, 2015), which could lead to functional changes in insulin-like growth factor 1 (IGF1). Interestingly, the stimulatory effect of IGF1 on GnRH release has been discovered (Hiney et al, 2009).…”

Undiscovered Roles for Transthyretin: From a Transporter Protein to a New Therapeutic Target for Alzheimer’s Disease

“…TTR was described as being involved in the regulation of insulin-like growth factor I (IGF-I) receptor in the hippocampus. TTR is able to increase IGF-I receptor levels, demonstrated in null and wild-type mice and in vitro-cultured cells [115]. Subsequently, it was found that TTR has a synergistic action with IGF-I over the IGF-I receptor, activating the Akt pathway, which is a specific IGF-I receptor signaling pathway [116].…”

Wilm’s tumor 1 promotes memory flexibility

“…Interestingly, another upregulated transcript encodes transthyretin (TTR), a protein that is involved with transport of retinol in the plasma and which plays an important role in neuroprotection 57 as well as memory consolidation and neurogenesis in the hippocampus 58,59 . Furthermore, TTR has also been shown to upregulate hippocampal expression of insulin-like growth factor receptor I (IGF-IR) and its nuclear translocation 60 .…”