Small-Molecule Targeted Aß42 Aggregate Degradation: Negatively Charged Small Molecules Are More Promising than the Neutral Ones.

Heavy evidence has confirmed that Aß42 oligomers are the most neurotoxic aggregates and play a critical role in the occurrence and development of Alzheimer's disease by causing functional neuron death, cognitive damage, and dementia. Disordered Aß42 oligomers are challenging therapeutic targets, and no drug is currently in clinical use that modifies the properties of their monomeric states. Here, a negatively charged molecule (ER), rather than the neutral TS1 one, is identified by a molecular dynamics simulation method to be more capable of binding and sequestering the intrinsically disordered amyloid-ß peptide Aß42 in its soluble pentameric state as well as its monomeric components. Results reveal that the ERs interact with Aß and inhibit the primary nucleation pathways in its aggregation process in entropic expansion mechanism for both Aß42 and Aß40 oligomers but with opposite characteristics of hydrophobic surface area (HSA). The interaction between Aß42 oligomer and either charged ER or neutral TS1/TS0 characterizes decreased HSA, and the decrease in ER-involved case is highly visible, consistent with the observations from in silico and in vitro studies. By contrast, the presence of these inhibitors causes the HSA of Aß40 oligomer to change undetectably and there is even a bit of increase in the histidine isomerized Aß40 oligomer. The HSA distinction between Aß42 and Aß40 oligomer is possibly derived from the different effects of M35-inhibitor interaction, which is analogous to the effect of M35 oxidation. In comparison with the neutral TS1/TS0 inhibitors, ER is more prone to bind the residues located in the central (ß1) and C-terminal (ß2) regions of Aß42 peptide, two key nucleation regions for Aß intramolecular folding, intermolecular aggregation, and assembly. Notably, ER can strongly bind the charged residues, such as K16, K28, D23, to greatly disturb the potential stabilizer (e.g., salt-bridge, etc.) in metastable Aß42 oligomers and protofibrils. These results illustrate the strategy of overcoming Alzheimer's disease from inhibiting its early stage Aß aggregation with two kinds of small molecules to alter their behavior for therapeutic purposes and strongly recommend paying more attention to the engineering and development of negatively charged inhibitors, the long-term underappreciated ones, targeting the early stage Aß aggregates.

Novel Disassembly Mechanisms of Sigmoid Aß42 Protofibrils by Introduced Neutral and Charged Drug Molecules.

Alzheimer's disease (AD) is characterized by fibrillar deposits of amyloid-ß (Aß) peptides and neurofibrillary tangles of Tau proteins. Aß peptides are composed of 37-49 residues, among which the Aß42 isoform is particularly toxic and aggregation-prone and is enriched in the plaques of AD brains and thus considered central to the development of AD. Therefore, disaggregation and disruption provide potential therapeutic approaches to reduce, inhibit, and even reverse Aß aggregation. Here we capture the atomic-level details of the interactions between sigmoid Aß42 fibril 2MXU or 5KK3 and either natural tanshinone compounds TS1 or TS0 or negatively charged ER, proposing two unprecedented disassembly mechanisms. Natural TS1 or TS0 prefers to insert into the cavity together with part at the surface of the 2MXU to open up the mouth and twist the conformation, destroying the ordered growth of subsequent monomers along the fibril axis. For the more compact two-fold 5KK3 , attachment of TS1 or TS0 at the surface including some inserted in cavity results in the separation of the two folds. In the two sigmoid fibril systems, it is no longer applicable for the routine criteria to assess Aß42 fibril disassembly by introduction of these drugs, such as either reduced H-bond number, decreased ß-sheet contents, or both. ER, like-charged to Aß42 fibril, is especially exceptional, and departs utterly from the neutral ones to disassemble Aß42 fibril. Besides the inapplicable routine criteria, positive binding energy between ER and Aß42 fibril also deviates from the hypotheses of "ligands exhibiting greater affinity for the ß-amyloid peptide are effective at altering its aggregation and inhibiting cell toxicity" ( Cairo et al. , Biochemistry 2002 , 41 , 8620 - 8629 ) but results in stronger disassembly effect on the two kinds of sigmoid Aß42 fibrils than neutral TS0 or TS1. The disassembly power of charged ER molecules derives from its stronger deformation ability to the conformation of Aß42 fibril than the neutral ones, twisting the one-fold 2MXU into tapered-shape and separating two-fold 5KK3 in two parts further, which is in great agreement with experimental observations ( Irwin et al. Biomacromolecules 2013 , 14 ( 1 ), 264 - 274 ). The unusual disassembly mechanisms fill the gaps and offer an alternative direction in engineering new inhibitors to treat AD.

Pyrolysis kinetics behavior of solid leather wastes.

In the leather industry, considerable amounts of non-recyclable solid leather wastes (SLWs) are produced and accumulated in factories. In this work, the non-isothermal thermochemical analysis (TGA) test was used to analyse the thermal degradation behaviour of chromium-tanned leather shaving, which is one of the main SLWs. The pyrolysis experiments were carried out under nitrogen atmosphere from 30 to 800 °C at different heating rates of 5, 10, 15 and 20 °C/min. Three different kinetic models, including the Flynn-Wall-Ozawa (FWO), Kissinger-Akahira-Sunose (KAS) and Kissinger methods, were used to calculate the kinetic parameters. The activation energy values calculated by FWO and KAS methods were 391.79 and 348.77 kJ/mol, respectively. In consideration of the high HHV (14.15 MJ/kg) and carbon productivity (10.15%), SLWs could represent a potential candidate material for bioenergy production and carbon preparation. These results could be used for the design of thermochemical conversion processes utilizing SLWs as feedstock.

An Original Monomer Sampling from a Ready-Made Aß42 NMR Fibril Suggests a Turn-ß-Strand Synergetic Seeding Mechanism.

Aggregation of amyloid beta (Aß) is a central step of Alzheimer's disease. Aß42 monomers are building blocks in the formation of both "on pathway" intermediate structures and "off pathway" oligomers. How to sample an Aß monomer becomes a problem however due to the instinct of Aß high flexibility and diversity as well as aggregation propensity. Currently, (1) most samplings focus on either the ready-made helix-rich 1Z0Q/1IYT NMR structure, or the completely extended conformation, but (2) few on a ready-made Aß NMR fibril (i. e., 2BEG). Here we compare the simulation results from sampling in scheme (1) with that in scheme (2), and find that the coil and ß-sheet contents in the 1Z0Q-sampled system are comparable to the counterparts in the 2BEG-sampled system, but with a large difference in simulation time and dynamics character. 1Z0Q-sampled system not only takes several times longer than the 2BEG-sampled one, and only ß1-seeding dynamics characteristic is observed probably due to far insufficient conformation transition in the limited simulation time. Two dynamics characteristics of Aß42 folding observed experimentally, that either ß1 region or ß2 region aggregates first, reproduce in the present simulations for 2BEG-sampled system however, suggesting a preferential sampling in the future simulation. In addition, a turn-ß-strand synergetic seeding mechanism of aggregation is first proposed based on the trajectory analyses on the four regions of Aß42 chain.