Retinol-Binding Protein Interferes with Transthyretin-Mediated β-Amyloid Aggregation Inhibition

Abstract

β-Amyloid (Aβ) aggregation is causally linked to Alzheimer's disease. On the basis of in vitro and transgenic animal studies, transthyretin (TTR) is hypothesized to provide neuroprotection against Aβ toxicity by binding to Aβ and inhibiting its aggregation. TTR is a homotetrameric protein that circulates in blood and cerebrospinal fluid; its normal physiological role is as a carrier for thyroxine and retinol-binding protein (RBP). RBP forms a complex with retinol, and the holoprotein (hRBP) binds with high affinity to TTR. In this study, the role of TTR ligands in TTR-mediated inhibition of Aβ aggregation was investigated. hRBP strongly reduced the ability of TTR to inhibit Aβ aggregation. The effect was not due to competition between Aβ and hRBP for binding to TTR, as Aβ bound equally well to TTR-hRBP complexes and TTR. hRBP is known to stabilize the TTR tetrameric structure. We show that Aβ partially destabilizes TTR and that hRBP counteracts this destabilization. Taken together, our results support a mechanism wherein TTR-mediated inhibition of Aβ aggregation requires not only TTR-Aβ binding but also destabilization of TTR quaternary structure.

WITHDRAWN: Association Between Retinol-binding Protein and Sarcopenia in General Inpatient Older Adults: a Cross Sectional Study

“…It transports vitamin A (retinol) from the liver to target tissues and constitutes the main regulator of circulating levels of retinol. RBP is transferred in the blood together with transthyretin (TTR), which prevents kidney ltration and retinol-binding protein catabolism [13] . According to Alkharfy et al, serum RBP4 levels correlated signi cantly well with the existing risk factors of cardiovascular disease in women, regardless of body [14] .…”

Potential Disrupting Effects of Wastewater-Derived Disinfection Byproducts on Chinese Rare Minnow (Gobiocypris rarus) Transthyretin: An In Vitro and In Silico Study

“…Five month-old Chinese rare minnows with a length of 36.6–41.0 mm were bought from Institute of Hydrobiology, Chinese Academy of Sciences (Wuhan, Hubei province, China). Considering that Chinese rare minnow is too small to sample blood, we use the liver for determination of the sequence and characterization of recombinant CrmTTR . Liver tissue specimens were immediately frozen and stored at −80 °C until use after harvesting.…”

“…Considering that Chinese rare minnow is too small to sample blood, we use the liver for determination of the sequence and characterization of recombinant CrmTTR. 48 Liver tissue specimens were immediately frozen and stored at −80 °C until use after harvesting. The critical procedures for determining the nucleotide sequences and amino acid sequences of CrmTTR were as follows: (a) the primers were designed according to the nucleotide sequences of fathead minnow TTR; (b) total RNA was purified from liver tissues with the RNA simple Total RNA Kit; (c) cDNA was generated from total RNA using the iScript cDNA Synthesis Kit; (d) the objective gene fragment was amplified and cloned into a vector in the hope of sequencing the nucleotide sequence.…”

Transthyretin: From Structural Stability to Osteoarticular and Cardiovascular Diseases

“…TTR has neuroprotective functions and/or is a stress response factor in various adverse conditions, including ischemia, Alzheimer’s disease (AD), Crohn’s disease, osteoarthritis, and preeclampsia [ 29 , 30 , 31 , 32 , 33 ]. Interestingly, RBP, by stabilizing TTR structure, reduces the inhibitory effect of TTR on Aβ aggregation [ 34 ]. In addition to neuroprotection and neurogenic activity, TTR is engaged in insulin secretion, autophagy, memory, and behavior [ 35 , 36 , 37 , 38 , 39 ].…”