Insights on the Interaction between Transthyretin and Aβ in Solution. A Saturation Transfer Difference (STD) NMR Analysis of the Role of Iododiflunisal

Gimeno, Ana; Santos, Luís Miguel; Alemi, Mobina; Rivas, Josep; Blasi, Daniel; Cotrina, Ellen Y; Llop, Jordi; Valencia, Gregorio; Cardoso, Isabel; Quintana, Jordi; Arsequell, Gemma; Jiménez‐Barbero, Jesús

doi:10.1021/acs.jmedchem.7b00428

Cited by 28 publications

(59 citation statements)

References 63 publications

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“…In this work, we have investigated the interaction between TTR and A β by using a segment (residues 1–28) of the full length A β peptide as it is more soluble and stable in buffer solutions. More importantly, however, A β (1–28) contains the hydrophobic core VFF (residues 18–20), which is recognized by TTR 7 , 23 . Furthermore, A β (1–28) holds the residues that chelate metal ions 31 and that can mediate the interaction between TTR and A β .…”

Section: Discussionmentioning

confidence: 99%

“…The structure of human TTR is well known 20 – 22 , and hypothetical models for its interaction with A β have been proposed. A recent NMR study places A β (12–28) within an external pocket spanning across the epigallocatechin-3-gallate (EGCG) binding site 23 . Previous studies positioned A β in the TTR interior pocket extending towards the short α -helix 7 , involving L110 and L82, since their mutation (L → A) destroys TTR’s ability to bind A β 24 .…”

Section: Introductionmentioning

confidence: 99%

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Copper mediated amyloid-β binding to Transthyretin

Ciccone

Fruchart-Gaillard

Mourier

et al. 2018

Sci Rep

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Transthyretin (TTR), a homotetrameric protein that transports thyroxine and retinol both in plasma and in cerebrospinal (CSF) fluid provides a natural protective response against Alzheimer’s disease (AD), modulates amyloid-β (Aβ) deposition by direct interaction and co-localizes with Aβ in plaques. TTR levels are lower in the CSF of AD patients. Zn2+, Mn2+ and Fe2+ transform TTR into a protease able to cleave Aβ. To explain these activities, monomer dissociation or conformational changes have been suggested. Here, we report that when TTR crystals are exposed to copper or iron salts, the tetramer undergoes a significant conformational change that alters the dimer-dimer interface and rearranges residues implicated in TTR’s ability to neutralize Aβ. We also describe the conformational changes in TTR upon the binding of the various metal ions. Furthermore, using bio-layer interferometry (BLI) with immobilized Aβ(1–28), we observe the binding of TTR only in the presence of copper. Such Cu2+-dependent binding suggests a recognition mechanism whereby Cu2+ modulates both the TTR conformation, induces a complementary Aβ structure and may participate in the interaction. Cu2+-soaked TTR crystals show a conformation different from that induced by Fe2+, and intriguingly, TTR crystals grown in presence of Aβ(1–28) show different positions for the copper sites from those grown its absence.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Copper mediated amyloid-β binding to Transthyretin

Ciccone

Fruchart-Gaillard

Mourier

et al. 2018

Sci Rep

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“…Hence, chemical stabilization of TTR has been proposed as a therapeutic avenue in AD. Interestingly, in the model put forward by Gimeno and co-workers, the stabilizer IDIF was capable of binding to TTR at the central pocket without affecting Aβ peptide binding [78].…”

Section: Transthyretin As Therapeutic Target In Alzheimer's Diseasementioning

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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“…With the aim of providing a prioritized list of compounds that help enhance the TTR/Aβ interaction, we started a drug discovery program using a combination of computational modeling, in vitro affinity/selectivity/stability assays and structural studies (35). One of these compounds, iododiflunisal (IDIF; Figure 1) has proven efficient in promoting Aβ clearance from the brain and improving animal's cognitive functions when orally administered to AD transgenic mice (AβPPswe/PS1A246E/TTR+/-) daily for 2 months, starting just before the onset of the disease (36).…”

Section: Introductionmentioning

confidence: 99%

Oral treatment with iododiflunisal delays beta amyloid plaque formation in a transgenic mouse model of Alzheimer Disease: a Longitudinal in vivo molecular imaging study

Rejc

Gómez‐Vallejo

Rios

et al. 2020

Preprint

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Background: Transthyretin (TTR) is a tetrameric, Amyloid-beta (Aβ)-binding protein, which has been shown to reduce Aβ toxicity both in vitro and in vivo. The ability of TTR to interact with Aβ can be enhanced by a series of small molecules that stabilize its tetrameric form. Because of this, TTR stabilizers might act as disease modifying drugs in Alzheimer Disease (AD). In this work, we monitored the therapeutic efficacy of two TTR stabilizers, iododiflunisal (IDIF) and the repurposed drug tolcapone, by longitudinal assessment of Aβ deposition in an animal model of AD using positron emission tomography (PET) with [ 18 F]florbetaben.Methods: Mice (AβPPswe/PS1A246E/TTR+/-; n=21) were divided into 3 groups (n=7 per group): iododiflunisal (IDIF)-treated, tolcapone-treated and non-treated. The treatment, administered in the drinking water at a dose of 100 mg/Kg/day, was started at 5 months of age. The level of Aβ deposition was assessed at ages=5, 9, 11, and 14 months by PET imaging using [ 18 F]florbetaben. Treatment efficacy was determined based on radiotracer uptake in the hippocampus (HIP) and the cortex (CTX) with respect to the cerebellum (CB) and presented as standardized uptake value ratios (SUVr). Immunohistochemical (IHC) analysis was performed at 14 months of age to further support in vivo results. Results: SUVr of [ 18 F]florbetaben in CTX and HIP of non-treated animals progressivelyincreased from age=5 to 11 months and stabilized afterwards. In contrast, [ 18 F]florbetaben uptake in HIP of IDIF-treated animals remained constant between ages=5 and 11 months and significantly increased at 14 months. At age=11 months, IDIF-treated group showed significantly lower SUVr values than those obtained for nontreated animals. In tolcapone-treated group, SUVr progressively increased with time, but at lower rate than in non-treated group. Moderate treatment effect of tolcapone suggests different mechanism of action than IDIF. No significant treatment effect was observed in CTX of IDIF-or tolcapone-treated animals. Results from IHC matched the in vivo data at age=14 months. Conclusions:The TTR stabilizer IDIF shows good Aβ-protective effect. Nevertheless, Aβ levels in treated and control animals reached similar values at the end of the study. Furthermore, differences in efficacy between IDIF and tolcapone, suggest different mechanisms of action.

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Insights on the Interaction between Transthyretin and Aβ in Solution. A Saturation Transfer Difference (STD) NMR Analysis of the Role of Iododiflunisal

Cited by 28 publications

References 63 publications

Copper mediated amyloid-β binding to Transthyretin

Copper mediated amyloid-β binding to Transthyretin

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

Oral treatment with iododiflunisal delays beta amyloid plaque formation in a transgenic mouse model of Alzheimer Disease: a Longitudinal in vivo molecular imaging study

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