The structure of tyrosine-10 favors ionic conductance of Alzheimer's disease-associated full-length amyloid-ß channels.

Amyloid ß (Aß) ion channels destabilize cellular ionic homeostasis, which contributes to neurotoxicity in Alzheimer's disease. The relative roles of various Aß isoforms are poorly understood. We use bilayer electrophysiology, AFM imaging, circular dichroism, FTIR and fluorescence spectroscopy to characterize channel activities of four most prevalent Aß peptides, Aß1-42, Aß1-40, and their pyroglutamylated forms (AßpE3-42, AßpE3-40) and correlate them with the peptides' structural features. Solvent-induced fluorescence splitting of tyrosine-10 is discovered and used to assess the sequestration from the solvent and membrane insertion. Aß1-42 effectively embeds in lipid membranes, contains large fraction of ß-sheet in a ß-barrel-like structure, forms multi-subunit pores in membranes, and displays well-defined ion channel features. In contrast, the other peptides are partially solvent-exposed, contain minimal ß-sheet structure, form less-ordered assemblies, and produce irregular ionic currents. These findings illuminate the structural basis of Aß neurotoxicity through membrane permeabilization and may help develop therapies that target Aß-membrane interactions.

Clothing impact on post-exercise comfort: skin-clothing physiology in transient environment.

Sportswear manufactured from hygroscopic fibres can absorb moisture during activity or intermittent exercise and may change the thermal management of clothing. This change in the thermal behaviour of the fabric can lead to buffer the post-exercise chill. During activity in a moderately cold environment clothing made of 100% wool fibre helps wearers to slow down evaporative and conductive cooling, which can provide more thermal and comfort sensation compared to 100% cotton, 100% viscose, and 100% polyester. Twelve males performed cycling in a controlled climate chamber of temperature: 15 ± 0.5 °C, and relative humidity (RH):50 ± 5% followed by a drying phase in a windy environment by wearing full-sleeve t-shirts. Wool shirt was observed to hold a greater torso skin temperature (p < 0.05) than the other fibre types. Participants were asked a range of comfort-related questions at varying intervals. The temperature sensation was found (p < 0.05) significant for wool clothing. Moreover, participants rated wool shirt significantly (p < 0.05) as more comfortable during the post-exercise phase.

Both clothing and physiological responses were investigated during exercise and post-exercise periods for male participants while wearing full-sleeve sportswear made of wool, cotton, viscose, and polyester. Wool clothing maintained a higher skin microclimate temperature and a warmer sensation, helping buffer the post-exercise chill.

Effects of Aß-derived peptide fragments on fibrillogenesis of Aß.

Amyloid ß (Aß) peptide aggregation plays a central role in Alzheimer's disease (AD) etiology. AD drug candidates have included small molecules or peptides directed towards inhibition of Aß fibrillogenesis. Although some Aß-derived peptide fragments suppress Aß fibril growth, comprehensive analysis of inhibitory potencies of peptide fragments along the whole Aß sequence has not been reported. The aim of this work is (a) to identify the region(s) of Aß with highest propensities for aggregation and (b) to use those fragments to inhibit Aß fibrillogenesis. Structural and aggregation properties of the parent Aß1-42 peptide and seven overlapping peptide fragments have been studied, i.e. Aß1-10 (P1), Aß6-15 (P2), Aß11-20 (P3), Aß16-25 (P4), Aß21-30 (P5), Aß26-36 (P6), and Aß31-42 (P7). Structural transitions of the peptides in aqueous buffer have been monitored by circular dichroism and Fourier transform infrared spectroscopy. Aggregation and fibrillogenesis were analyzed by light scattering and thioflavin-T fluorescence. The mode of peptide-peptide interactions was characterized by fluorescence resonance energy transfer. Three peptide fragments, P3, P6, and P7, exhibited exceptionally high propensity for ß-sheet formation and aggregation. Remarkably, only P3 and P6 exerted strong inhibitory effect on the aggregation of Aß1-42, whereas P7 and P2 displayed moderate inhibitory potency. It is proposed that P3 and P6 intercalate between Aß1-42 molecules and thereby inhibit Aß1-42 aggregation. These findings may facilitate therapeutic strategies of inhibition of Aß fibrillogenesis by Aß-derived peptides.

Mutual structural effects of unmodified and pyroglutamylated amyloid ß peptides during aggregation.

Amyloid ß (Aß) peptide aggregates are linked to Alzheimer's disease (AD). Posttranslationally pyroglutamylated Aß (pEAß) occurs in AD brains in significant quantities and is hypertoxic, but the underlying structural and aggregation properties remain poorly understood. Here, the structure and aggregation of Aß1-40 and pEAß3-40 are analyzed separately and in equimolar combination. Circular dichroism data show that Aß1-40 , pEAß3-40 , and their combination assume α-helical structure in dry state and transition to unordered structure in aqueous buffer. Aß1-40 and the 1:1 combination gradually acquire ß-sheet structure while pEAß3-40 adopts an α-helix/ß-sheet conformation. Thioflavin-T fluorescence studies suggest that the two peptides mutually inhibit fibrillogenesis. Fourier transform infrared (FTIR) spectroscopy identifies the presence of ß-turn and α-helical structures in addition to ß-sheet structure in peptides in aqueous buffer. The kinetics of transitions from the initial α-helical structure to ß-sheet structure were resolved by slow hydration of dry peptides by D2 O vapor, coupled with isotope-edited FTIR. These data confirmed the mutual suppression of ß-sheet formation by the two peptides. Remarkably, pEAß3-40 maintained a significant fraction of α-helical structure in the combined sample, implying a reduced ß-sheet propensity of pEAß3-40 . Altogether, the data imply that the combination of unmodified and pyroglutamylated Aß peptides resists fibrillogenesis and favors the prefibrillar state, which may underlie hypertoxicity of pEAß.

Quercetin-3-Rutinoside Blocks the Disassembly of Cholera Toxin by Protein Disulfide Isomerase.

Protein disulfide isomerase (PDI) is mainly located in the endoplasmic reticulum (ER) but is also secreted into the bloodstream where its oxidoreductase activity is involved with thrombus formation. Quercetin-3-rutinoside (Q3R) blocks this activity, but its inhibitory mechanism against PDI is not fully understood. Here, we examined the potential inhibitory effect of Q3R on another process that requires PDI: disassembly of the multimeric cholera toxin (CT). In the ER, PDI physically displaces the reduced CTA1 subunit from its non-covalent assembly in the CT holotoxin. This is followed by CTA1 dislocation from the ER to the cytosol where the toxin interacts with its G protein target for a cytopathic effect. Q3R blocked the conformational change in PDI that accompanies its binding to CTA1, which, in turn, prevented PDI from displacing CTA1 from its holotoxin and generated a toxin-resistant phenotype. Other steps of the CT intoxication process were not affected by Q3R, including PDI binding to CTA1 and CT reduction by PDI. Additional experiments with the B chain of ricin toxin found that Q3R could also disrupt PDI function through the loss of substrate binding. Q3R can thus inhibit PDI function through distinct mechanisms in a substrate-dependent manner.