| 1. |
- Abelein, Axel, et al.
(författare)
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The hairpin conformation of the amyloid beta peptide is an important structural motif along the aggregation pathway
- 2014
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Ingår i: Journal of Biological Inorganic Chemistry. - : Springer Science and Business Media LLC. - 0949-8257 .- 1432-1327. ; 19:4-5, s. 623-634
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Forskningsöversikt (refereegranskat)abstract
- The amyloid beta (A beta) peptides are 39-42 residue-long peptides found in the senile plaques in the brains of Alzheimer's disease (AD) patients. These peptides self-aggregate in aqueous solution, going from soluble and mainly unstructured monomers to insoluble ordered fibrils. The aggregation process(es) are strongly influenced by environmental conditions. Several lines of evidence indicate that the neurotoxic species are the intermediate oligomeric states appearing along the aggregation pathways. This minireview summarizes recent findings, mainly based on solution and solid-state NMR experiments and electron microscopy, which investigate the molecular structures and characteristics of the A beta peptides at different stages along the aggregation pathways. We conclude that a hairpin-like conformation constitutes a common motif for the A beta peptides in most of the described structures. There are certain variations in different hairpin conformations, for example regarding H-bonding partners, which could be one reason for the molecular heterogeneity observed in the aggregated systems. Interacting hairpins are the building blocks of the insoluble fibrils, again with variations in how hairpins are organized in the cross-section of the fibril, perpendicular to the fibril axis. The secondary structure propensities can be seen already in peptide monomers in solution. Unfortunately, detailed structural information about the intermediate oligomeric states is presently not available. In the review, special attention is given to metal ion interactions, particularly the binding constants and ligand structures of A beta complexes with Cu(II) and Zn(II), since these ions affect the aggregation process(es) and are considered to be involved in the molecular mechanisms underlying AD pathology.
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| 2. |
- Gemmi, Mauro, et al.
(författare)
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3D Electron Diffraction : The Nanocrystallography Revolution
- 2019
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Ingår i: ACS central science. - : American Chemical Society (ACS). - 2374-7943 .- 2374-7951. ; 5:8, s. 1315-1329
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Tidskriftsartikel (refereegranskat)abstract
- Crystallography of nanocrystalline materials has witnessed a true revolution in the past 10 years, thanks to the introduction of protocols for 3D acquisition and analysis of electron diffraction data. This method provides single-crystal data of structure solution and refinement quality, allowing the atomic structure determination of those materials that remained hitherto unknown because of their limited crystallinity. Several experimental protocols exist, which share the common idea of sampling a sequence of diffraction patterns while the crystal is tilted around a noncrystallographic axis, namely, the goniometer axis of the transmission electron microscope sample stage. This Outlook reviews most important 3D electron diffraction applications for different kinds of samples and problematics, related with both materials and life sciences. Structure refinement including dynamical scattering is also briefly discussed.
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| 3. |
- Luo, Jinghui, et al.
(författare)
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Alzheimer Peptides Aggregate into Transient Nanoglobules That Nucleate Fibrils
- 2014
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 53:40, s. 6302-6308
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Tidskriftsartikel (refereegranskat)abstract
- Protein/peptide oligomerization, cross-beta strand fibrillation, and amyloid deposition play a critical role in many diseases, but despite extensive biophysical characterization, the structural and dynamic details of oligomerization and fibrillation of amyloidic peptides/proteins remain to be fully clarified. Here, we simultaneously monitored the atomic, molecular, and mesoscopic states of aggregating Alzheimer's amyloid beta (A beta) peptides over time, using a slow aggregation protocol and a fast aggregation protocol, and determined the cytotoxicity of the intermediate states. We show that in the early stage of fast fibrillation (the lag phase) the A beta peptides coalesced into apparently unstructured globules (15-200 nm in diameter), which slowly grew larger. Then a sharp transition occurred, characterized by the first appearance of single fibrillar structures of approximately >= 100 nm. These fibrils emerged from the globules. Simultaneously, an increase was observed for the cross-beta strand conformation that is characteristic of the fibrils that constitute mature amyloid. The number and size of single fibrils rapidly increased. Eventually, the fibrils coalesced into mature amyloid. Samples from the early lag phase of slow fibrillation conditions were especially toxic to cells, and this toxicity sharply decreased when fibrils formed and matured into amyloid. Our results suggest that the formation of fibrils may protect cells by reducing the toxic structures that appear in the early lag phase of fibrillation.
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| 4. |
- Luo, Jinghui, et al.
(författare)
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Cellular Polyamines Promote Amyloid-Beta (A beta) Peptide Fibrillation and Modulate the Aggregation Pathways
- 2013
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Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 4:3, s. 454-462
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Tidskriftsartikel (refereegranskat)abstract
- The cellular polyamines spermine, spermidine, and their metabolic precursor putrescine, have long been associated with cell-growth, tumor-related gene regulations, and Alzheimer's disease. Here, we show by in vitro spectroscopy and AFM imaging, that these molecules promote aggregation of amyloid-beta (A beta) peptides into fibrils and modulate the aggregation pathways. NMR measurements showed that the three polyamines share a similar binding mode to monomeric A beta(1-40) peptide. Kinetic ThT studies showed that already very low polyamine concentrations promote amyloid formation: addition of 10 mu M spermine (normal intracellular concentration is similar to 1 mM) significantly decreased the lag and transition times of the aggregation process. Spermidine and putrescine additions yielded similar but weaker effects. CD measurements demonstrated that the three polyamines induce different aggregation pathways, involving different forms of induced secondary structure. This is supported by AFM images showing that the three polyamines induce A beta(1-40) aggregates with different morphologies. The results reinforce the notion that designing suitable ligands which modulate the aggregation of A beta peptides toward minimally toxic pathways may be a possible therapeutic strategy for Alzheimer's disease.
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| 5. |
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| 6. |
- Luo, Jinghui, et al.
(författare)
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Cross-interactions between the Alzheimer Disease Amyloid-beta Peptide and Other Amyloid Proteins : A Further Aspect of the Amyloid Cascade Hypothesis
- 2016
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 291:32, s. 16485-16493
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Forskningsöversikt (refereegranskat)abstract
- Many protein folding diseases are intimately associated with accumulation of amyloid aggregates. The amyloid materials formed by different proteins/peptides share many structural similarities, despite sometimes large amino acid sequence differences. Some amyloid diseases constitute risk factors for others, and the progression of one amyloid disease may affect the progression of another. These connections are arguably related to amyloid aggregates of one protein being able to directly nucleate amyloid formation of another, different protein: the amyloid cross-interaction. Here, we discuss such cross-interactions between the Alzheimer disease amyloid-beta (A beta) peptide and other amyloid proteins in the context of what is known from in vitro and in vivo experiments, and of what might be learned from clinical studies. The aim is to clarify potential molecular associations between different amyloid diseases. We argue that the amyloid cascade hypothesis in Alzheimer disease should be expanded to include cross-interactions between A beta and other amyloid proteins.
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| 7. |
- Luo, Jinghui, et al.
(författare)
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Endogenous Polyamines Reduce the Toxicity of Soluble A beta Peptide Aggregates Associated with Alzheimer's Disease
- 2014
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Ingår i: Biomacromolecules. - : American Chemical Society (ACS). - 1525-7797 .- 1526-4602. ; 15:6, s. 1985-1991
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Tidskriftsartikel (refereegranskat)abstract
- Polyamines promote the formation of the A beta peptide amyloid fibers that are a hallmark of Alzheimer's disease. Here we show that polyamines interact with nonaggregated A beta peptides, thereby reducing the peptide's hydrophobic surface. We characterized the associated conformational change through NMR titrations and molecular dynamics simulations. We found that even low concentrations of spermine, sperimidine, and putrescine fully protected SH-SY5Y (a neuronal cell model) against the most toxic conformational species of AA even at an A beta oligomer concentration that would otherwise kill half of the cells or even more. These observations lead us to conclude that polyamines interfere with the more toxic prefibrillar conformations and might protect cells by promoting the structural transition of A beta toward its less toxic fibrillar state that we reported previously. Since polyamines are present in brain fluid at the concentrations where we observed all these effects, their activity needs to be taken into account in understanding the molecular processes related to the development of Alzheimer's disease.
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| 8. |
- Luo, Jinghui, et al.
(författare)
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Human lysozyme inhibits the in vitro aggregation of A beta peptides, which in vivo are associated with Alzheimer's disease
- 2013
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Ingår i: Chemical Communications. - : Royal Society of Chemistry (RSC). - 1359-7345 .- 1364-548X. ; 49:58, s. 6507-6509
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease is a neurodegenerative disorder characterized by accumulation of A beta peptide aggregates in the brain. Using ThT fluorescence assays, AFM imaging, NMR and CD spectroscopy, and MD modeling we show that lysozyme - a hydrolytic enzyme abundant in human secretions - completely inhibits the aggregation of A beta peptides at equimolar lysozyme : A beta peptide ratios.
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| 9. |
- Luo, Jinghui, et al.
(författare)
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Inhibiting and Reversing Amyloid-β Peptide (1-40) Fibril Formation with Gramicidin S and Engineered Analogues
- 2013
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Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 19:51, s. 17338-17348
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Tidskriftsartikel (refereegranskat)abstract
- In Alzheimer's disease, amyloid-β (Aβ) peptides aggregate into extracellular fibrillar deposits. Although these deposits may not be the prime cause of the neurodegeneration that characterizes this disease, inhibition or dissolution of amyloid fibril formation by Aβ peptides is likely to affect its development. ThT fluorescence measurements and AFM images showed that the natural antibiotic gramicidin S significantly inhibited Aβ amyloid formation in vitro and could dissolve amyloids that had formed in the absence of the antibiotic. In silico docking suggested that gramicidin S, a cyclic decapeptide that adopts a β-sheet conformation, binds to the Aβ peptide hairpin-stacked fibril through β-sheet interactions. This may explain why gramicidin S reduces fibril formation. Analogues of gramicidin S were also tested. An analogue with a potency that was four-times higher than that of the natural product was identified.
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| 10. |
- Luo, Jinghui, et al.
(författare)
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Non-chaperone Proteins Can Inhibit Aggregation and Cytotoxicity of Alzheimer Amyloid beta Peptide
- 2014
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 289:40, s. 27766-27775
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Tidskriftsartikel (refereegranskat)abstract
- Background: A amyloid formation is associated with Alzheimer disease. Results: Non-chaperone proteins prevent amyloid formation and reduce the cytotoxicity of the A peptide. Conclusion: Non-chaperone proteins may affect the onset and development of Alzheimer disease by interfering with A peptide aggregation. Significance: Non-chaperone proteins can function as a chaperone protein to regulate the pathway of the A fibrillation in proteostasis providing a new strategy in the treatment of Alzheimer disease. Many factors are known to influence the oligomerization, fibrillation, and amyloid formation of the A peptide that is associated with Alzheimer disease. Other proteins that are present when A peptides deposit in vivo are likely to have an effect on these aggregation processes. To separate specific versus broad spectrum effects of proteins on A aggregation, we tested a series of proteins not reported to have chaperone activity: catalase, pyruvate kinase, albumin, lysozyme, -lactalbumin, and -lactoglobulin. All tested proteins suppressed the fibrillation of Alzheimer A(1-40) peptide at substoichiometric ratios, albeit some more effectively than others. All proteins bound non-specifically to A, stabilized its random coils, and reduced its cytotoxicity. Surprisingly, pyruvate kinase and catalase were at least as effective as known chaperones in inhibiting A aggregation. We propose general mechanisms for the broad-spectrum inhibition A fibrillation by proteins. The mechanisms we discuss are significant for prognostics and perhaps even for prevention and treatment of Alzheimer disease.
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