Evidence for synergistic action of transthyretin and IGF-I over the IGF-I receptor

Vieira, Marta; Leal, Sónia S.; Gomes, Cláudio M.; Saraiva, Maria João

doi:10.1016/j.bbadis.2016.01.008

Cited by 7 publications

(5 citation statements)

References 48 publications

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“…IGF-1 supplementation did not modulate hippocampal expression of IGF1R or IGF1 or its downstream signaling elements at P5 and P9, indicating that physiological IGF-1 signaling in the brain was maintained. On the other hand, it cannot be excluded that the transient downregulation of TTR mRNA, encoding protein transthyretin, might negatively affect hippocampal IGF1R expression ( Vieira et al, 2015 ), as it is known to act synergistically with IGF-1 on IGF1R activation ( Vieira et al, 2016 ). Alternatively, the transient alterations in the expression of IGF-1 and related genes might arise before P5, as it was recently shown for IGF-1 expression in the choroid plexus of preterm rabbit pups treated with IGF-1/IGFBP3 complex ( Gram et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Insulin-Like Growth Factor-1 Supplementation Promotes Brain Maturation in Preterm Pigs

Christiansen

Holmqvist

Pan

et al. 2023

eNeuro

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Very preterm infants show low levels of insulin-like growth factor-1 (IGF-1), which is associated with postnatal growth restriction and poor neurological outcomes. It remains unknown whether supplemental IGF-1 may stimulate neurodevelopment in preterm neonates. Using cesarean-delivered preterm pigs as a model of preterm infants, we investigated the effects of supplemental IGF-1 on motor function and regional and cellular brain development. Pigs were treated with 2.25 mg/kg/day of recombinant human IGF-1/IGF binding protein 3 complex from birth until Day 5 or 9 before collection of brain samples for quantitative immunohistochemistry (IHC), RNA-seq and qPCR analyses. Brain protein synthesis was measured using in vivo labeling with [2H5] phenylalanine. We showed that the IGF-1 receptor was widely distributed in the brain and largely coexisted with immature neurons. Region-specific quantification of IHC labeling showed that IGF-1 treatment promoted neuronal differentiation, increased subcortical myelination, and attenuated synaptogenesis in a region- and time-dependent manner. The expression levels of genes involved in neuronal and oligodendrocyte maturation, angiogenic and transport functions were altered, reflecting enhanced brain maturation in response to IGF-1 treatment. Cerebellar protein synthesis was increased by 19% at Day 5 and 14% at Day 9 after IGF-1 treatment. Treatment had no effect on Iba1-positive microglia or regional brain weights and did not affect motor development or the expression of genes related to IGF-1 signaling. In conclusion, the data show that supplemental IGF-1 promotes brain maturation in newborn preterm pigs. The results provide further support for IGF-1 supplementation therapy in the early postnatal period in preterm infants.SIGNIFICANCE STATEMENTDeficiency of systemic insulin-like growth factor-1 (IGF-1) is associated with delayed neurological development in preterm infants. Here, we show that the IGF-1 receptor is primarily expressed in immature neurons in the developing brain of the translational preterm pig model. Supplementation with IGF-1 accelerates neuron differentiation in the hippocampus and promotes myelination in subcortical white matter regions in a time-dependent way. Furthermore, systemic IGF-1 supplementation stimulates cerebral protein synthesis. Our study suggests that IGF-1 therapy in the early postnatal period might be supportive for neurodevelopment in preterm infants.

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Section: Discussionmentioning

confidence: 99%

Insulin-Like Growth Factor-1 Supplementation Promotes Brain Maturation in Preterm Pigs

Christiansen

Holmqvist

Pan

et al. 2023

eNeuro

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“…Recent studies have demonstrated that TTR may act via the IGF-IR signalling pathway synergistically with IGFI [ 44 ]. However, our results revealed that supplementation with IGF-I did not affect metabolism of neither the FM-treated nor the CM-treated cells.…”

Section: Discussionmentioning

confidence: 99%

Neuron-derived transthyretin modulates astrocytic glycolysis in hormone-independent manner

et al. 2017

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It has been shown that neurons alter the expression of astrocytic metabolic enzymes by secretion of until now unknown molecule(s) into extracellular fluid. Here, we present evidence that neuron-derived transthyretin (TTR) stimulates expression of glycolytic enzymes in astrocytes which is reflected by an increased synthesis of ATP. The action of TTR is restricted to regulatory enzymes of glycolysis: phosphofructokinase P (PFKP) and pyruvate kinase M1/M2 isoforms (PKM1/2). The regulation of PFK and PKM expression by TTR is presumably specific for brain tissue and is independent of the role of TTR as a carrier protein for thyroxine and retinol. TTR induced expression of PKM and PFK is mediated by the cAMP/PKA-dependent pathway and is antagonized by the PI3K/Akt pathway. Our results provide the first experimental evidence for action of TTR as a neuron-derived energy metabolism activator in astrocytes and describe the mechanisms of its action. The data presented here suggest that TTR is involved in a mechanism in which neurons stimulate degradation of glycogen-derived glucosyl units without significant modulation of glucose uptake by glial cells.

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“…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].…”

Section: Transthyretin As a Gene Regulatormentioning

confidence: 99%

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

Gião

Saavedra

Cotrina³

et al. 2020

IJMS

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Transthyretin (TTR), an homotetrameric protein mainly synthesized by the liver and the choroid plexus, and secreted into the blood and the cerebrospinal fluid, respectively, has been specially acknowledged for its functions as a transporter protein of thyroxine and retinol (the latter through binding to the retinol-binding protein), in these fluids. Still, this protein has managed to stay in the spotlight as it has been assigned new and varied functions. In this review, we cover knowledge on novel TTR functions and the cellular pathways involved, spanning from neuroprotection to vascular events, while emphasizing its involvement in Alzheimer’s disease (AD). We describe details of TTR as an amyloid binding protein and discuss its interaction with the amyloid Aβ peptides, and the proposed mechanisms underlying TTR neuroprotection in AD. We also present the importance of translating advances in the knowledge of the TTR neuroprotective role into drug discovery strategies focused on TTR as a new target in AD therapeutics.

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Evidence for synergistic action of transthyretin and IGF-I over the IGF-I receptor

Cited by 7 publications

References 48 publications

Insulin-Like Growth Factor-1 Supplementation Promotes Brain Maturation in Preterm Pigs

Insulin-Like Growth Factor-1 Supplementation Promotes Brain Maturation in Preterm Pigs

Neuron-derived transthyretin modulates astrocytic glycolysis in hormone-independent manner

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

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