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amyloid oligomer

Waldemar Hoffmann, Kristin Folmert, Johann Moschner, Xing Huang, Hans von Berlepsch, Beate Koksch, Michael T Bowers, Gert von Helden, Kevin Pagel
The hexapeptide NFGAIL is a highly amyloidogenic peptide, derived from the human islet amyloid polypeptide (hIAPP). Recent investigations indicate that presumably soluble hIAPP oligomers are one of the cytotoxic species in type II diabe-tes. Here we use Thioflavin T staining, transmission electron microscopy as well as ion mobility-mass spectrometry coupled to infrared (IR) spectroscopy to study the amyloid formation mechanism and the quaternary- and secondary-structure of soluble NFGAIL oligomers. Our data reveal that at neutral pH NFGAIL follows a nucleation-dependent mechanism to form amyloid fibrils...
December 13, 2017: Journal of the American Chemical Society
Bogdan Barz, Qinghua Liao, Birgit Strodel
One of the the main research topics related to Alzheimer's disease is the aggregation of the amyloid-β peptide, which was shown to follow different pathways for the two major alloforms of the peptide, Aβ40 and the more toxic Aβ42. Experimental studies emphasized that oligomers of specific sizes appear in the early aggregation process in different quantities and might be the key toxic agents for each of the two alloforms. We use transition networks derived from all-atom molecular dynamics simulations to show that the oligomers leading to the type of oligomer distributions observed in experiments originate from compact conformations...
December 13, 2017: Journal of the American Chemical Society
Naoya Itoh, Eri Takada, Kaori Okubo, Yoshiaki Yano, Masaru Hoshino, Akira Sasaki, Masataka Kinjo, Katsumi Matsuzaki
The formation of neurotoxic aggregates by amyloid-β peptide (Aβ) is considered to be a key step in the onset of Alzheimer's disease. It is widely accepted that oligomers are more neurotoxic than amyloid fibrils in the aqueous-phase aggregation of Aβ. Membrane-mediated amyloidogenesis is also relevant to the pathology, although the relationship between the aggregate size and cytotoxicity has remained elusive. Here, the aggregational processes of Aβ on living cells and cytotoxic events were monitored by fluorescence techniques...
December 13, 2017: Chembiochem: a European Journal of Chemical Biology
Charles R Watts, Andrew Gregory, Cole Frisbie, Sándor Lovas
The conformational space and structural ensembles of amyloid beta (Aβ) peptides and their oligomers in solution are inherently disordered and proven to be challenging to study. Optimum force field selection for molecular dynamics (MD) simulations and the biophysical relevance of results are still unknown. We compared the conformational space of the Aβ(1-40) dimers by 300 ns replica exchange MD simulations at physiological temperature (310 K) using: the AMBER-ff99sb-ILDN, AMBER-ff99sb*-ILDN, AMBER-ff99sb-NMR, and CHARMM22* force fields...
December 13, 2017: Proteins
Clelia Galati, Natalia Spinella, Lucio Renna, Danilo Milardi, Francesco Attanasio, Michele Francesco Maria Sciacca, Corrado Bongiorno
Although the formation of β-amyloid (Aβ) fibrils in neuronal tissues is a hallmark of Alzheimer disease (AD), small-sized Aβ oligomers rather than mature fibrils have been identified as the most neurotoxic species. Therefore, the design of new inhibitors, able to prevent the aggregation of Aβ, is believed to be a promising therapeutic approach to AD. Unfortunately, the short-lived intermediate structures that occur in a solution along the Aβ aggregation pathway escape conventional experimental investigations and there is urgent need of new tools aimed at the discovery of agents targeting monomeric Aβ and blocking the early steps of amyloid aggregation...
2017: Beilstein Journal of Nanotechnology
Liping Chen, Chunhui Huang, Jieyi Shentu, Minjun Wang, Sicheng Yan, Fei Zhou, Zaijun Zhang, Chuang Wang, Yifan Han, Qinwen Wang, Wei Cui
Indirubins are natural occurring alkaloids extracted from indigo dye-containing plants. Indirubins could inhibit various kinases, and might be used to treat chronic myelocytic leukemia, cancer and neurodegenerative disorders. 7-bromoindirubin-3-oxime (7Bio), an indirubin derivative derived from indirubin-3-oxime, possesses inhibitory effects against cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3β (GSK3β), two pharmacological targets of Alzheimer's disease (AD). In this study, we have discovered that 2...
2017: Frontiers in Molecular Neuroscience
Gefei Chen, Axel Abelein, Harriet E Nilsson, Axel Leppert, Yuniesky Andrade-Talavera, Simone Tambaro, Lovisa Hemmingsson, Firoz Roshan, Michael Landreh, Henrik Biverstål, Philip J B Koeck, Jenny Presto, Hans Hebert, André Fisahn, Jan Johansson
Protein misfolding and aggregation is increasingly being recognized as a cause of disease. In Alzheimer's disease the amyloid-β peptide (Aβ) misfolds into neurotoxic oligomers and assembles into amyloid fibrils. The Bri2 protein associated with Familial British and Danish dementias contains a BRICHOS domain, which reduces Aβ fibrillization as well as neurotoxicity in vitro and in a Drosophila model, but also rescues proteins from irreversible non-fibrillar aggregation. How these different activities are mediated is not known...
December 12, 2017: Nature Communications
Juris Kiskis, Istvan Horvath, Pernilla Wittung-Stafshede, Sandra Rocha
Amyloid formation of the synaptic brain protein α-synuclein (αS) is related to degeneration of dopaminergic neurons in Parkinson's disease patients. αS is thought to function in vesicle transport and fusion and it binds strongly to negatively charged vesicles in vitro. Here we combined circular dichroism, fluorescence and imaging methods in vitro to characterize the interaction of αS with negatively charged vesicles of DOPS (1,2-dioleoyl-sn-glycero-3-phospho-L-serine, sodium salt) and DOPG (1,2-dioleoyl-sn-glycero-3-phospho-(1'-rac-glycerol), sodium salt) and the consequences of such interactions on αS amyloid formation...
January 2017: Quarterly Reviews of Biophysics
Alexander Korn, Steffane McLennan, Juliane Adler, Martin Krueger, Dayana Surendran, Sudipta Maiti, Daniel Huster
The formation of the hydrophobic contact between phenylalanine 19 (F19) and leucine 34 (L34) of amyloid β (1-40) (Aβ(1-40)) is known to be an important step in the fibrillation of Aβ(1-40) peptides. Mutations of this putatively early molecular contact were shown to strongly influence the toxicity of Aβ(1-40) (Das et al., ACS Chem. Neurosci. 6 (2015) 1290-1295). Any mutation of residue F19 completely abolished the toxicity of Aβ(1-40), suggesting that a proper F19 - L34 contact is crucial also for the formation of transient oligomers...
December 12, 2017: ACS Chemical Neuroscience
Elena Schartmann, Sarah Schemmert, Tamar Ziehm, Leonie H E Leithold, Nan Jiang, Markus Tusche, N Jon Shah, Karl-Josef Langen, Janine Kutzsche, Dieter Willbold, Antje Willuweit
Alzheimer's disease (AD), until now, is an incurable progressive neurodegenerative disease. To target toxic amyloid β oligomers in AD patients' brains and to convert them into non-toxic aggregation-incompetent species, we designed peptides consisting solely of d-enantiomeric amino acid residues. The original lead compound was named D3 and several D3 derivatives were designed to enhance beneficial properties. Here, we compare four d-peptides concerning their efficiency to pass the blood-brain barrier (BBB)...
December 7, 2017: European Journal of Pharmaceutical Sciences
Justin P Lomont, Kacie L Rich, Michał Maj, Jia-Jung Ho, Joshua S Ostrander, Martin T Zanni
We use 2D IR spectroscopy to explore fibril formation for the two predominant isoforms of the β-amyloid (Aβ1-40 and Aβ1-42) protein associated with Alzheimer's disease. 2D IR spectra resolve a transition at 1610 cm-1 in Aβ fibrils that does not appear in other Aβ aggregates, even those with predominantly β-sheet structure like oligomers. This transition is not resolved in linear IR spectroscopy, because it lies under the broad band centered at 1625 cm-1 that is the traditional infrared signature for amy-loid fibrils...
December 8, 2017: Journal of Physical Chemistry. B
Carlotta Marasini, Bente Vestergaard
Protein fibrillation is associated with a number of fatal amyloid diseases (e.g. Alzheimer's and Parkinson's diseases). From a structural point of view, the aggregation process starts from an ensemble of native states that convert into transiently formed oligomers, higher order assemblies and protofibrils and, finally, fibrils. The different species exist in equilibrium in solution leading to a high degree of sample heterogeneity. It is impossible to physically isolate any single species for structural analysis: separation will alter the equilibrium and potentially cause structural changes...
2017: Advances in Experimental Medicine and Biology
Eri Chatani, Naoki Yamamoto
Amyloid fibrils are supramolecular protein assemblies with a fibrous morphology and cross-β structure. The formation of amyloid fibrils typically follows a nucleation-dependent polymerization mechanism, in which a one-step nucleation scheme has widely been accepted. However, a variety of oligomers have been identified in early stages of fibrillation, and a nucleated conformational conversion (NCC) mechanism, in which oligomers serve as a precursor of amyloid nucleation and convert to amyloid nuclei, has been proposed...
December 6, 2017: Biophysical Reviews
Yong Wang, Yun Shi, Huafeng Wei
Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the most common cause of dementia among aged people whose population is rapidly increasing. AD not only seriously affects the patient's physical health and quality of life, but also adds a heavy burden to the patient's family and society. It is urgent to understand AD pathogenesis and develop the means of prevention and treatment. AD is a chronic devastating neurodegenerative disease without effective treatment. Current approaches for management focus on helping patients relieve or delay the symptoms of cognitive dysfunction...
August 2017: Journal of Alzheimer's Disease and Parkinsonism
Tamás Vajda, András Perczel
The crucial role of water in amyloid-β(Aβ) fibril proteins is evaluated in several ways including the water's thermodynamic and kinetic solvation effects. As regards the water's character, its hindered-rotation barriers are also considered. The following protein molecules considered here are: the Aβ40 (PDB ID: 2LMN), Aβ42 (PDB ID: 5KK3 and 2NAO) and the double-layered Aβ17-42 fibril. We discuss: (i) extracellular Aβ40 and Aβ42 fibril monomers exhibit an ambivalent propensity to transform into a helical form toward the N-term region and a β-strand-like form near the C-terminal; (ii) interfacial water molecules play a crucial role in protein-protein interactions, as molecular dynamics simulations have shown a significant impact on the protein-protein binding; (iii) it is shown that the spontaneous dimerization process of the Aβ42 fibril protein in water occurs via a two-step nucleation-accommodation mechanism; (iv) MD simulations of the double-layered Aβ17-42 fibril model show that the C↔C interface appears more energetically favorable than the N↔N interface due to large hydrophobic contacts; (v) the water's role in the HET-s prion and in the Aβ fibrillar aggregates; (vi) it was found that the monomer-oligomer equilibrium spontaneously dissociates into stable monomeric species when they are incubated up to 3 μm for a longer time (>1 week) in a physiological buffer...
December 20, 2017: Biomolecular Concepts
Abeer Alghamdi, Vladislav Vyshemirsky, David J S Birch, Olaf J Rolinski
Aggregation of beta-amyloids is one of key processes responsible for the development of Alzheimer's desease. Early molecular-level detection of beta-amyloid oligomers may help in early diagnosis and in the development of new intervention therapies. Our previous studies on changes in beta-amyloid's single tyrosine intrinsic fluorescence response during aggregation demonstrated a four-exponential fluorescence intensity decay, and that the ratio of the pre-exponential factors indicated the extent of aggregation in the early stages of the process before the beta-sheets are formed...
December 6, 2017: Methods and Applications in Fluorescence
Ana Martinez Hernandez, Hendrik Urbanke, Alan L Gillman, Joon Lee, Sergey Ryazanov, Hope Y Agbemenyah, Eva Benito, Gaurav Jain, Lalit Kaurani, Gayane Grigorian, Andrei Leonov, Nasrollah Rezaei-Ghaleh, Petra Wilken, Fernando Teran Arce, Jens Wagner, Martin Fuhrman, Mario Caruana, Angelique Camilleri, Neville Vassallo, Markus Zweckstetter, Roland Benz, Armin Giese, Anja Schneider, Martin Korte, Ratnesh Lal, Christian Griesinger, Gregor Eichele, Andre Fischer
Alzheimer's disease is a devastating neurodegenerative disease eventually leading to dementia. An effective treatment does not yet exist. Here we show that oral application of the compound anle138b restores hippocampal synaptic and transcriptional plasticity as well as spatial memory in a mouse model for Alzheimer's disease, when given orally before or after the onset of pathology. At the mechanistic level, we provide evidence that anle138b blocks the activity of conducting Aβ pores without changing the membrane embedded Aβ-oligomer structure...
December 5, 2017: EMBO Molecular Medicine
Nataliya R Rovnyagina, Nikolai N Sluchanko, Tatiana N Tikhonova, Victor V Fadeev, Artur Yu Litskevich, Alexander A Maskevich, Evgeny A Shirshin
Amyloid fibrils formation is the well-known hallmark of various neurodegenerative diseases. Thioflavin T (ThT)-based fluorescence assays are widely used to detect and characterize fibrils, however, if performed in bioliquids, the analysis can be biased due to the presence of other, especially abundant, proteins. Particularly, it is known that albumin may bind ThT, although the binding mechanism remains debatable. Here the role of low-order albumin oligomers in ThT binding is investigated using time-resolved fluorometry and size-exclusion chromatography...
December 2, 2017: International Journal of Biological Macromolecules
O Elaskalani, I Khan, M Morici, C Matthysen, M Sabale, R N Martins, G Verdile, P Metharom
The effects of the Alzheimer's disease (AD)-associated Amyloid-β (Aβ) peptides on platelet aggregation have been previously assessed, but most of these studies focused on Aβ40 species. It also remains to be determined which distinct forms of Aβ peptides exert differential effects on platelets. In AD, oligomeric Aβ42 species is widely thought to be a major contributor to the disease pathogenesis. We, therefore, examine the ability of oligomeric and fibrillary Aβ42 to affect platelet aggregation. We show that both forms of Aβ42 induced significant platelet aggregation and that it is a novel ligand for the platelet receptor GPVI...
December 5, 2017: Platelets
Nathan L Maris, Dylan Shea, Alissa Bleem, James D Bryers, Valerie Daggett
There has been much interest in synthetic peptides as inhibitors of aggregation associated with amyloid diseases. Of particular interest are compounds that target the cytotoxic soluble oligomers preceding the formation of mature, nontoxic fibrils. This study explores physical and chemical differences between two de novo designed peptides that share an identical primary structure but differ in backbone chirality at six key positions. We show that the presence of alternating L-/D-amino acid motifs dramatically increases aqueous solubility, enforces α-sheet secondary structure, inhibits ag-gregation of the β-amyloid peptide implicated in Alz-heimer's Disease, in addition to neutralizing its cytotox-icity...
December 4, 2017: Biochemistry
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