Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/852715

The inhibition of cellular toxicity of amyloid-beta by dissociated transthyretin

Saelices, L.·Cao, Q.·Anderson, D. H.·Liang, W. Y.·Chou, J.·Eisenberg, D. S.
View original source ↗Export metadata ↓

Abstract

The protective effect of transthyretin (TTR) on cellular toxicity of amyloid-beta (A{beta}) has been previously reported. TTR is a tetrameric carrier of thyroxine in blood and cerebrospinal fluid, whose pathogenic aggregation causes systemic amyloidosis. In contrast, many reports have shown that TTR binds amyloid-beta (A{beta}), associated with Alzheimers disease, alters its aggregation, and inhibits its toxicity both in vitro and in vivo. In this study, we question whether TTR amyloidogenic ability and its anti-amyloid inhibitory effect are associated. Our results indicate that the dissociation of the TTR tetramer, required for its amyloid pathogenesis, is also necessary to prevent cellular toxicity from A{beta} oligomers. These findings suggest that the A{beta} binding site of TTR may be hidden in its tetrameric form. Aided by computational docking and peptide screening, we identified a TTR segment that is capable of altering A{beta} aggregation and toxicity, mimicking TTR cellular protection. This segment inhibits A{beta} oligomer formation and also promotes the formation of non-toxic, non-amyloid, amorphous aggregates which are more sensitive to protease digestion. This segment also inhibits seeding of A{beta} catalyzed by A{beta} fibrils extracted from the brain of an Alzheimers patient. Our results suggest that mimicking the inhibitory effect of TTR with peptide-based therapeutics represents an additional avenue to explore for the treatment of Alzheimers disease. Significance statementThe pathological landmarks of Alzheimers disease are the formation of amyloid plaques and neurofibrillary tangles. Amyloid plaques contain fibrous structures made of aggregated amyloid-beta (A{beta}). In 1982, Shirahama and colleagues observed the presence of transthyretin (TTR) in these plaques. TTR is a tetrameric protein whose aggregation causes transthyretin amyloidosis. However, TTR protects A{beta} from aggregating and causing toxicity to neurons. In this study, we show that the dissociation of TTR tetramers is required to inhibit cellular toxicity caused by A{beta}. In addition, we identified a minimum segment of TTR that inhibits A{beta} aggregation and cellular toxicity by the formation of amorphous aggregates that are sensitive to proteases, similar to the natural effect of TTR found by others in vivo.

Source connections

Explore related subjects

biochemistryPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Saelices, L., Cao, Q., Anderson, D. H., Liang, W. Y., Chou, J., Eisenberg, D. S.. 2019-11-25. The inhibition of cellular toxicity of amyloid-beta by dissociated transthyretin. https://doi.org/10.1101/852715

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Modular assembly of mitochondrial complex III from a dynamic matrix domain pool

Mitochondrial complex III is a central component of the cellular energy metabolism. It is an obligate dimer of catalytic and accessory subunits that are encoded by two genomes. How its large matrix domain, formed by the core proteins Qcr1 and Qcr2, is built and joined to the membrane part and during assembly is not known. Here we show that Qcr1 and Qcr2 preassemble independently of complex III into matrix domain modules. Cryo-EM structures from a cardiolipin-deficient yeast strain and of recombinant protein resolved single, double and triple matrix domains, which are linked by the C-terminal tail of Qcr1. In the mature complex III, the same tail binds cytochrome b and cardiolipin. The modules form a dynamic pool, in which assembly species interconvert and exchange subunits. Mutations at the module interfaces, including mimics of human disease variants, reshape this pool and deletion of the Qcr1 tail impairs respiratory growth. Substitution of a tyrosine residue linked to parkinsonism exposes a conserved cysteine residue to oxidation. A cryo-EM structure of an assembly intermediate shows a cap of two matrix domains bound to a monomeric membrane module of cytochrome b, Qcr7, Qcr8 and cytochrome c1. We propose that complex III receives its matrix domain from a dynamic pool of prebuilt modules, which organizes the dimerization of the complex.

biochemistry↗
bioRxiv2026

Vasopressin V2 receptor phosphopeptide reshapes the conformational landscape of arrestin-2 beyond C-tail detachment

Binding of phosphorylated GPCR tails influences arrestin conformation, but the contribution of this interaction to the interdomain rotation associated with activation remains incompletely characterised. In particular, it remains unclear whether displacement of the arrestin C-tail is sufficient to favor larger interdomain rotations or whether the bound phosphotail exerts an additional effect on the conformational landscape. Here, we used enhanced-sampling simulations to characterise the conformational free-energy landscapes of basal (unbound) and V2Rpp-bound arrestin-2. We find that V2Rpp binding broadened the range of energetically accessible interdomain rotation angles relative to basal arrestin-2. However, the pronounced rotation observed in the experimental structures, while accessible, was not strongly favored. Strikingly, C-tail displacement alone does not reproduce this effect, as arrestin-2 retains a strong preference for small interdomain rotation angles in the absence of V2Rpp. Moreover, the C-tail-detached state is energetically unfavorable in the absence of V2Rpp. Together, these findings quantify the effects of V2Rpp binding on the interdomain rotation of arrestin-2 and disentangle the effects of phosphopeptide binding from those of C-tail detachment.

biochemistry↗
bioRxiv2026

Interventional breath analysis reveals oral microbial conversion of 1,2-Propanediol into Propanal and 1-Propanol

Background: Orally exhaled breath contains volatile organic compounds (VOCs) that may reflect local microbial metabolism as well as systemic processes. Consequently, the breath sampling route can influence VOC profiles and complicate biomarker interpretation. Previous studies have shown that 1-propanol is substantially enriched in orally compared with nasally exhaled breath. Objective: To determine whether a controlled oral challenge with 1,2-propanediol (1,2-PD) induces sampling route-dependent changes in breath 1-propanol concentrations. Methods: Ten healthy volunteers received 0.1 mL 1,2-PD diluted in approximately 50 mL water. The solution was used as an oral rinse for approximately 30 s and then expectorated. Matched oral and nasal end-tidal breath samples were collected before administration, immediately afterwards, and at 15-min intervals. Propanal, 1-propanol, acetol, acetone, and isoprene were analysed using gas chromatograph-ion mobility spectrometer (GC-IMS). Results: Oral 1,2-PD exposure produced a rapid and transient increase in exhaled propanal and 1-propanol signals, with the largest responses immediately after administration and at the second post-intervention measurement. In contrast, nasal signals remained comparatively stable. Acetone and isoprene showed no consistent intervention-related changes, regardless of the sampling route. No reproducible increase in acetol was detected, although interpretation was limited by analytical interference. Conclusion: A controlled oral 1,2-PD challenge elicited a route-specific propanal and 1-propanol response, consistent with local microbial metabolism of 1,2-PD within the oral cavity. Both fucose and 1,2-PD have been previously reported in human saliva, including elevated concentrations in selected disease-associated contexts. Bacteria can degrade salivary mucin glycans, releasing sugars including fucose. Together, these observations motivate investigation of a proposed pathway linking mucin-derived fucose to 1,2-PD and subsequent propanal and 1-propanol formation in the human oral cavity.

biochemistry↗