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

Gião, Tiago; Saavedra, Joana; Cotrina, Ellen Y; Quintana, Jordi; Llop, Jordi; Arsequell, Gemma; Cardoso, Isabel

doi:10.3390/ijms21062075

Cited by 51 publications

(55 citation statements)

References 124 publications

(146 reference statements)

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“…As occurred with ApoJ, Ttr expression levels peaked during the night (active period) in both intact male and female animals. The recognized influence of TTR in the promotion of Aβ binding/degradation in the brain [ 39 ], suggests that the observed 24-h circadian pattern of expression in the CP promotes the clearance of Aβ during the active period (nocturnal clearance), and not during sleep as previously anticipated. These results, although contradictory at first sight, strengthened the evidence for the presence of both a dependent- and independent-sleep mechanism of Aβ clearance in the brain [ 40 ].…”

Section: Discussionmentioning

confidence: 84%

Age, Sex Hormones, and Circadian Rhythm Regulate the Expression of Amyloid-Beta Scavengers at the Choroid Plexus

Duarte

Furtado

Hrynchak

et al. 2020

IJMS

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Accumulation of amyloid-beta (Aβ) in the brain is thought to derive from the impairment of Aβ clearance mechanisms rather than from its overproduction, which consequently contributes to the development of Alzheimer’s disease. The choroid plexus epithelial cells constitute an important clearance route for Aβ, either by facilitating its transport from the cerebrospinal fluid to the blood, or by synthesizing and secreting various proteins involved in Aβ degradation. Impaired choroid plexus synthesis, secretion, and transport of these Aβ-metabolizing enzymes have been therefore associated with the disruption of Aβ homeostasis and amyloid load. Factors such as aging, female gender, and circadian rhythm disturbances are related to the decline of choroid plexus functions that may be involved in the modulation of Aβ-clearance mechanisms. In this study, we investigated the impact of age, sex hormones, and circadian rhythm on the expression of Aβ scavengers such as apolipoprotein J, gelsolin, and transthyretin at the rat choroid plexus. Our results demonstrated that mRNA expression and both intracellular and secreted protein levels of the studied Aβ scavengers are age-, sex-, and circadian-dependent. These data suggest that the Aβ-degradation and clearance pathways at the choroid plexus, mediated by the presence of Aβ scavengers, might be compromised as a consequence of aging and circadian disturbances. These are important findings that enhance the understanding of Aβ-clearance-regulating mechanisms at the blood–cerebrospinal fluid barrier.

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Section: Discussionmentioning

confidence: 84%

Age, Sex Hormones, and Circadian Rhythm Regulate the Expression of Amyloid-Beta Scavengers at the Choroid Plexus

Duarte

Furtado

Hrynchak

et al. 2020

IJMS

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“…The T4-binding sites at the weaker of the two dimer–dimer interfaces of TTR are largely unoccupied in human blood and CSF [ 6 ]. TTR likely has additional unknown functions, especially in the brain [ 7 ]. In fact, TTR is also known as a neuroprotective protein in Alzheimer’s disease (AD) [ 8 , 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Repurposing Benzbromarone for Familial Amyloid Polyneuropathy: A New Transthyretin Tetramer Stabilizer

Cotrina¹,

Oliveira

Leite

et al. 2020

IJMS

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Transthyretin (TTR) is a homotetrameric protein involved in human amyloidosis, including familial amyloid polyneuropathy (FAP). Discovering small-molecule stabilizers of the TTR tetramer is a therapeutic strategy for these diseases. Tafamidis, the only approved drug for FAP treatment, is not effective for all patients. Herein, we discovered that benzbromarone (BBM), a uricosuric drug, is an effective TTR stabilizer and inhibitor against TTR amyloid fibril formation. BBM rendered TTR more resistant to urea denaturation, similarly to iododiflunisal (IDIF), a very potent TTR stabilizer. BBM competes with thyroxine for binding in the TTR central channel, with an IC50 similar to IDIF and tafamidis. Results obtained by isothermal titration calorimetry (ITC) demonstrated that BBM binds TTR with an affinity similar to IDIF, tolcapone and tafamidis, confirming BBM as a potent binder of TTR. The crystal structure of the BBM-TTR complex shows two molecules binding deeply in the thyroxine binding channel, forming strong intermonomer hydrogen bonds and increasing the stability of the TTR tetramer. Finally, kinetic analysis of the ability of BBM to inhibit TTR fibrillogenesis at acidic pH and comparison with other stabilizers revealed that benzbromarone is a potent inhibitor of TTR amyloidogenesis, adding a new interesting scaffold for drug design of TTR stabilizers.

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“…2 Accumulating evidence suggests that TTR may play an auxiliary role in sequestering -amyloid (A) peptides within the CSF by promoting their clearance from the CNS to the periphery, potentially providing neuroprotective effects against Alzheimer's disease (AD). [3][4][5] In systemic circulation, a significant portion of circulating TTR (approximately 50%) forms a macromolecular complex with retinol binding protein 4 (RBP4) associated with all-trans-retinol (vitamin A, 2). 6,7 This retinol-dependent RBP4-TTR interaction is essential for efficient systemic trafficking of 2 as it prevents glomerular filtration of the low molecular weight RBP4-alltrans-retinol complex (holo-RBP4).…”

Section: Introductionmentioning

confidence: 99%

Identification of Transthyretin Tetramer Kinetic Stabilizers That Are Capable of Inhibiting the Retinol-Dependent Retinol Binding Protein 4-Transthyretin Interaction

Cioffi¹,

Raja²,

Muthuraman³

et al. 2021

Preprint

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Dissociation of transthyretin (TTR) tetramers may lead to misfolding and aggregation of pro-amyloidogenic monomers, which underlies TTR amyloidosis (ATTR) pathophysiology. ATTR is a progressive disease resulting from the deposition of toxic fibrils in tissues that predominantly presents clinically as amyloid cardiomyopathy and peripheral polyneuropathy. Ligands that bind to and kinetically stabilize TTR tetramers prohibit their dissociation and may prevent ATTR onset. Drawing from clinically investigated AG10, we designed a constrained congener (18a) that exhibits excellent TTR tetramer binding potency, prevents TTR aggregation in a gel-based assay, and possesses desirable pharmacokinetics in mice. Additionally, 18a significantly lowers murine serum retinol-binding protein 4 (RBP4) levels despite a lack of binding at that protein’s all-trans-retinol site. We hypothesize that kinetic stabilization of TTR tetramers via 18a is allosterically hindering all-trans-retinol-dependent RBP4-TTR tertiary complex formation and that the compound could present ancillary therapeutic utility for indications treated with RBP4 antagonists, such as macular degeneration.

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

Cited by 51 publications

References 124 publications

Age, Sex Hormones, and Circadian Rhythm Regulate the Expression of Amyloid-Beta Scavengers at the Choroid Plexus

Age, Sex Hormones, and Circadian Rhythm Regulate the Expression of Amyloid-Beta Scavengers at the Choroid Plexus

Repurposing Benzbromarone for Familial Amyloid Polyneuropathy: A New Transthyretin Tetramer Stabilizer

Identification of Transthyretin Tetramer Kinetic Stabilizers That Are Capable of Inhibiting the Retinol-Dependent Retinol Binding Protein 4-Transthyretin Interaction

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