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101.
Amyloid Fibrils form Hybrid Colloidal Gels and Aerogels with Dispersed CaCO3 Nanoparticles
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New hybrid colloidal gels are reported formed by amyloid fibrils and CaCO3 nanoparticles (CaNPs), with Ca2+ as charge screening ions and CaNPs as physical crosslinking agents to establish and stabilize the network. The gel is characterized by rheological measurements and diffusing wave spectroscopy, complemented by microscopic observations using transmission and scanning electron microscopy. The hybrid colloidal gels show a two orders of magnitude improved gel strength at significantly shorter gelation times compared to previous calcium ion‐induced amyloid fibril gels. Supercritical CO2‐dried colloidal aerogels allow demonstrating that amyloid fibrils, combined with smaller (higher specific surface area) CaNPs, constitute a denser fibrils network, resulting in stronger gels. By varying the amyloid fibril concentration and the CaNPs size and concentration, the complete phase diagram is mapped out. This enables identifying the sol–gel phase transition and a window for gel formation, which widens with increasing CaNPs size. Finally pH responsiveness and self‐healing properties of this hybrid colloidal gel are also demonstrated, making these systems a suitable candidate for biological applications. 相似文献
102.
Mingzhen Zhang Baiping Ren Hong Chen Yan Sun Jie Ma Binbo Jiang Jie Zheng 《Israel journal of chemistry》2017,57(7-8):586-601
The misfolding and aggregation of proteins and peptides into amyloid fibrils are believed to be responsible for the dysfunction and death of neuron cells in many neurodegenerative diseases. Resolving the atomic structures of amyloid peptides at different aggregation stages by molecular simulations has opened new ways to probe the molecular mechanisms of amyloid aggregation, toxicity, and inhibition, as well as to validate computational data with available experimental ones. In this review article, we summarize some recent and important findings on: 1) a number of atomic structures of amyloid oligomers with typical β-sheet-rich conformations, related to amyloid aggregation; 2) different amyloid peptide-induced membrane-disruption mechanisms, related to amyloid toxicity; and 3) rational design of different amyloid inhibitors capable of preventing amyloid aggregation and toxicity, related to amyloid inhibition. All these findings will provide some mechanistic implications for molecular mechanisms of amyloid aggregation, toxicity, and inhibition, which are fundamentally and practically important for the treatment of amyloid diseases. 相似文献
103.
B. Saremi M. Mielenz M.M. Rahman A. Hosseini C. Kopp S. Dänicke F. Ceciliani H. Sauerwein 《Journal of dairy science》2013
Serum amyloid A3 (SAA3) is the predominant SAA isoform secreted by mammary epithelial cells in dairy cows; it is also expressed in bovine adipose tissue (AT). The adipokine SAA3 is linked to obesity and insulin resistance of AT and the respective inflammatory response, at least in mice. Dietary treatment with conjugated linoleic acids (CLA) reportedly also affects insulin sensitivity and inflammatory status in monogastrics. Both SAA3 and CLA thus seem to alter similar functions. Based on changes in insulin sensitivity and the inflammatory status throughout lactation, we hypothesized that the mRNA abundance of SAA3 in various tissues might be regulated as well and that CLA could be a modulator of SAA3 mRNA expression. In 2 trials, 21 pluriparous and 25 primiparous Holstein cows were fed 100 g/d of a CLA or a control fat supplement from d 1 to 182 or 105 postpartum, respectively. Biopsies from liver and subcutaneous (s.c.) AT from pluriparous cows and samples from 3 different visceral AT and 3 s.c. AT, muscle, mammary gland, and liver tissue from slaughtered primiparous cows were obtained. In an adipocyte cell culture system, cell samples were collected during differentiation of bovine preadipocytes at d 0, 2, 6, 8, 10, 12, and 13 relative to the onset of differentiation. The SAA3 mRNA abundance in tissues and in differentiating bovine preadipocytes was measured by real-time PCR. The presence of the SAA protein was confirmed by Western blotting. Treatment with CLA yielded only few and inconsistent effects on SAA3 mRNA abundance. In both trials, SAA3 mRNA peaked at d 1 postpartum in all tissues except in mesenteric AT, in which the change was not significant. The highest SAA3 mRNA expression was observed in the mammary gland, followed by omental AT. The SAA protein was present in the visceral and s.c. AT depots investigated. Adipocytes as one source of SAA3 were confirmed by the SAA3 mRNA profile in differentiating adipocytes. The longitudinal changes observed point to SAA3 being involved in the inflammatory situation around parturition. 相似文献
104.
105.
Jillian E. Smith Chen Liang Michael Tseng Noel Li Sha Li Allisandra K. Mowles Anil K. Mehta David G. Lynn 《Israel journal of chemistry》2015,55(6-7):763-769
Structurally defined cross-β assemblies have allowed for the development of basis sets for isotope-edited infrared spectra to follow progressive assembly over time. These basis sets, composed of a minimal number of individual spectra, are sufficient to identify the populations of polymorphs evolving throughout the assembly process. This approach provides, for the first time, the spectral assignment and relative distribution of paracrystalline intermediates formed from the intermolecular molten globule phase where nucleation occurs. Using the basis sets, we can now follow how subtle changes in assembly energetics impact the accessible polymorphs along the assembly pathway. Here, simple methylation of the Gln22 side chain of the nucleating core of the Dutch mutant of the Aβ of Alzheimer’s disease, Aβ(16-22)E22Q, dramatically increases the distribution of sampled polymorphs and slows progression to the final thermodynamic assembly. These data establish that amyloid cross-β structures can assemble through a dynamic conformational phylogeny. This fluid context-dependent network, so accessible to simple peptides, may provide the basis for the conformational selection and evolution of the complex supramolecular assemblies implicated in the many protein misfolding and prion diseases. 相似文献
106.
Single‐Molecule Imaging Reveals that Small Amyloid‐β1–42 Oligomers Interact with the Cellular Prion Protein (PrPC)
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Kristina A. Ganzinger Dr. Priyanka Narayan Dr. Seema S. Qamar Dr. Laura Weimann Dr. Rohan T. Ranasinghe Prof. Adriano Aguzzi Prof. Christopher M. Dobson Dr. James McColl Dr. Peter St. George‐Hyslop Prof. David Klenerman 《Chembiochem : a European journal of chemical biology》2014,15(17):2515-2521
Oligomers of the amyloid‐β peptide (Aβ) play a central role in the pathogenesis of Alzheimer’s disease and have been suggested to induce neurotoxicity by binding to a plethora of cell‐surface receptors. However, the heterogeneous mixtures of oligomers of varying sizes and conformations formed by Aβ42 have obscured the nature of the oligomeric species that bind to a given receptor. Here, we have used single‐molecule imaging to characterize Aβ42 oligomers (oAβ42) and to confirm the controversial interaction of oAβ42 with the cellular prion protein (PrPC) on live neuronal cells. Our results show that, at nanomolar concentrations, oAβ42 interacts with PrPC and that the species bound to PrPC are predominantly small oligomers (dimers and trimers). Single‐molecule biophysical studies can thus aid in deciphering the mechanisms that underlie receptor‐mediated oAβ‐induced neurotoxicity, and ultimately facilitate the discovery of novel inhibitors of these pathways. 相似文献
107.
A Cyclic KLVFF‐Derived Peptide Aggregation Inhibitor Induces the Formation of Less‐Toxic Off‐Pathway Amyloid‐β Oligomers
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Tadamasa Arai Dr. Daisuke Sasaki Takushi Araya Dr. Takeshi Sato Dr. Youhei Sohma Prof. Motomu Kanai 《Chembiochem : a European journal of chemical biology》2014,15(17):2577-2583
Inhibition of amyloid‐β (Aβ) aggregation could be a target of drug development for the treatment of currently incurable Alzheimer's disease. We previously reported that a head‐to‐tail cyclic peptide of KLVFF (cyclic‐KLVFF), a pentapeptide fragment corresponding to the Aβ16–20 region (which plays a critical role in the generating Aβ fibrils), possesses potent inhibitory activity against Aβ aggregation. Here we found that the inhibitory activity of cyclic‐KLVFF was significantly improved by incorporating an additional phenyl group at the β‐position of the Phe4 side chain (inhibitor 3 ). Biophysical and biochemical analyses revealed the rapid formation of 3 ‐embedded oligomer species when Aβ1–42 was mixed with 3 . The oligomer species is an “off‐pathway” species with low affinity for cross‐β‐sheet‐specific dye thioflavin T and oligomer‐specific A11 antibodies. The oligomer species had a sub‐nanometer height and little capability of aggregation to amyloid fibrils. Importantly, the toxicity of the oligomer species was significantly lower than that of native Aβ oligomers. These insights will be useful for further refinement of cyclic‐KLVFF‐based aggregation inhibitors. 相似文献
108.
Kirilka Mladenova Georgi Stavrakov Irena Philipova Mariyana Atanasova Svetla Petrova Jordan Doumanov Irini Doytchinova 《International journal of molecular sciences》2021,22(14)
Misfolded amyloid beta (Aβ) peptides aggregate and form neurotoxic oligomers. Membrane and mitochondrial damages, calcium dysregulation, oxidative stress, and fibril deposits are among the possible mechanisms of Aβ cytotoxicity. Galantamine (GAL) prevents apoptosis induced by Aβ mainly through the ability to stimulate allosterically the α7 nAChRs and to regulate the calcium cytosolic concentration. Here, we examined the cytoprotective effects of two GAL derivatives, namely compounds 4b and 8, against Aβ cytotoxicity on the human neuroblastoma cell line SH-SY5Y. The protective effects were tested at simultaneous administration, pre-incubation and post-incubation, with Aβ. GAL and curcumin (CU) were used in the study as reference compounds. It was found that 4b protects cells in a similar mode as GAL, while compound 8 and CU potentiate the toxic effects of Aβ. Allosteric stimulation of α7 nAChRs is suggested as a possible mechanism of the cytoprotectivity of 4b. These and previous findings characterize 4b as a prospective non-toxic multi-target agent against neurodegenerative disorders with inhibitory activity on acetylcholinesterase, antioxidant, and cytoprotective properties. 相似文献
109.
Hu Y Su B Kim CS Hernandez M Rostagno A Ghiso J Kim JR 《Chembiochem : a European journal of chemical biology》2010,11(17):2409-2418
Aggregation of β-amyloid (Aβ) is implicated in the pathology of Alzheimer's disease. Development of a robust strategy to detect Aβ oligomeric intermediates, which have been identified as significant toxic agents, would be highly beneficial in the screening of drug candidates as well as enhancing our understanding of Aβ oligomerization. Rapid, specific and quantitative detection, currently unavailable, would be highly preferred for accurate and reliable probing of transient Aβ oligomers. Here, we report the development of a novel peptide probe, PG46, based on the nature of Aβ self-assembly and the conformation-sensitive fluorescence of the biarsenical dye, FlAsH. PG46 was found to bind to Aβ oligomers and displayed an increase in FlAsH fluorescence upon binding. No such event was observed when PG46 was co-incubated with Aβ low-molecular-weight species or Aβ fibrils. Aβ oligomer detection was fast, and occurred within one hour without any additional sample incubation or preparation. We anticipate that the development of a strategy for detection of amyloid oligomers described in this study will be directly relevant to a host of other amyloidogenic proteins. 相似文献
110.