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amyloid oligomer

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https://www.readbyqxmd.com/read/29928798/spontaneous-fluctuations-can-guide-drug-design-strategies-for-structurally-disordered-proteins
#1
Barun Kumar Maity, Vicky Vishvakarma, Dayana Surendran, Anoop Rawat, Anirban Das, Shreya Pramanik, Najmul Arfin, Sudipta Maiti
Structure-based 'rational' drug-design strategies fail for diseases associated with intrinsically disordered proteins (IDPs). However, structural disorder allows large amplitude spontaneous intramolecular dynamics in a protein. We demonstrate a method that exploits this dynamics to provide quantitative information about the degree of interaction of an IDP with other molecules. A candidate ligand molecule may not bind strongly, but even momentary interactions can be expected to perturb the fluctuations. We measure the amplitude and frequency of the equilibrium fluctuations of fluorescently labeled small oligomers of hIAPP (an IDP associated with Type II diabetes) in a physiological solution, using nanosecond fluorescence cross-correlation spectroscopy...
June 21, 2018: Biochemistry
https://www.readbyqxmd.com/read/29924502/crucial-role-of-protein-oligomerization-in-the-pathogenesis-of-alzheimer-s-and-parkinson-s-diseases
#2
REVIEW
Minee L Choi, Sonia Gandhi
Misfolding and aggregation of the proteins amyloid-β (Aβ), tau and alpha-synuclein (α-syn) is the predominant pathology underlying the neurodegenerative disorders, Alzheimer's and Parkinson's disease. Whilst end stage insoluble products of aggregation have been well characterised in human and animal models of disease, accumulating evidence from biophysical, cellular and in vivo studies has shown that soluble intermediates of aggregation, or oligomers, may be the key species that mediate toxicity and underlie seeding and spreading in disease...
June 20, 2018: FEBS Journal
https://www.readbyqxmd.com/read/29914551/immunotherapy-to-improve-cognition-and-reduce-pathological-species-in-an-alzheimer-s-disease-mouse-model
#3
Krystal Herline, Frances Prelli, Pankaj Mehta, Claire MacMurray, Fernando Goñi, Thomas Wisniewski
BACKGROUND: Alzheimer's disease (AD) is characterized by physiologically endogenous proteins amyloid beta (Aβ) and tau undergoing a conformational change and accumulating as soluble oligomers and insoluble aggregates. Tau and Aβ soluble oligomers, which contain extensive β-sheet secondary structure, are thought to be the most toxic forms. The objective of this study was to determine the ability of TWF9, an anti-β-sheet conformation antibody (aβComAb), to selectively recognize pathological Aβ and phosphorylated tau in AD human tissue compared with cognitively normal age-matched controls and to improve the performance of old 3xTg-AD mice with advanced pathology in behavioral testing after acute treatment with TWF9...
June 18, 2018: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/29911185/new-applications-of-solid-state-nmr-in-structural-biology
#4
Patrick C A van der Wel
Various recent developments in solid-state nuclear magnetic resonance (ssNMR) spectroscopy have enabled an array of new insights regarding the structure, dynamics, and interactions of biomolecules. In the ever more integrated world of structural biology, ssNMR studies provide structural and dynamic information that is complementary to the data accessible by other means. ssNMR enables the study of samples lacking a crystalline lattice, featuring static as well as dynamic disorder, and does so independent of higher-order symmetry...
April 20, 2018: Emerging Topics in Life Sciences
https://www.readbyqxmd.com/read/29906099/parkinson-s-disease-associated-%C3%AE-synuclein-familial-mutants-promote-dopaminergic-neuronal-death-in-drosophila-melanogaster
#5
Ganesh M Mohite, Saumya Dwivedi, Subhadeep Das, Rakesh Kumar, Sravya Paluri, Surabhi Mehra, Neha Ruhela, Arunima S, Narendra Nath Jha, Samir K Maji
α-Synuclein (α-Syn) aggregation and amyloid formation are associated with loss of dopaminergic neurons in Parkinson's disease (PD). In addition, familial mutations in α-Syn are shown to be one of the definite causes of PD. Here we have extensively studied familial PD associated α-Syn G51D, H50Q and E46K mutations using Drosophila model system. Our data showed that flies expressing α-Syn familial mutants have a shorter lifespan and exhibit more climbing defects compared to wild-type (WT) flies in an age-dependent manner...
June 15, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29902934/update-on-biomarkers-for-amyloid-pathology-in-alzheimer-s-disease
#6
Nicholas J Ashton, Michael Schöll, Kerstin Heurling, Eleni Gkanatsiou, Erik Portelius, Kina Höglund, Gunnar Brinkmalm, Abdul Hye, Kaj Blennow, Henrik Zetterberg
At the center of Alzheimer's disease pathogenesis is the aberrant aggregation of amyloid-β (Aβ) into oligomers, fibrils and plaques. Effective monitoring of Aβ deposition directly in patients is essential to assist anti-Aβ therapeutics in target engagement and participant selection. In the advent of approved anti-Aβ therapeutics, biomarkers will become of fundamental importance in initiating treatments having disease modifying effects at the earliest stage. Two well-established Aβ biomarkers are widely utilized: Aβ-binding ligands for positron emission tomography and immunoassays to measure Aβ42 in cerebrospinal fluid...
June 15, 2018: Biomarkers in Medicine
https://www.readbyqxmd.com/read/29899186/gnetin-c-a-resveratrol-dimer-reduces-amyloid-%C3%AE-1-42-a%C3%AE-42-production-and-ameliorates-a%C3%AE-42-lowered-cell-viability-in-cultured-sh-sy5y-human-neuroblastoma-cells
#7
Syota Seino, Takeru Kimoto, Hidemi Yoshida, Kunikazu Tanji, Tomoh Matsumiya, Ryo Hayakari, Kazuhiko Seya, Shogo Kawaguchi, Kazushi Tsuruga, Hiroshi Tanaka, Tadaatsu Imaizumi
Accumulation and oligomerization of amyloid-beta (Aβ) peptides have been known to be a potent cause of neurodegenerative diseases such as Alzheimer's disease (AD). To expand the possibilities of preventing AD, we investigated the effects of resveratrol dimers, gnetin C and ε-viniferin, on Aβ 1-42 (Aβ42) production and the reduced cell viability observed after Aβ42 treatment (monomers, 10 μM) in cultured SH-SY5Y human neuroblastoma cells. Among them, addition of gnetin C (20 μM) into the media reduced Aβ42 production most efficiently...
2018: Biomedical Research
https://www.readbyqxmd.com/read/29898386/camkii-metaplasticity-drives-a%C3%AE-oligomer-mediated-synaptotoxicity
#8
Patricio Opazo, Silvia Viana da Silva, Mario Carta, Christelle Breillat, Steven J Coultrap, Dolors Grillo-Bosch, Matthieu Sainlos, Françoise Coussen, K Ulrich Bayer, Christophe Mulle, Daniel Choquet
Alzheimer's disease (AD) is emerging as a synaptopathology driven by metaplasticity. Indeed, reminiscent of metaplasticity, oligomeric forms of the amyloid-β peptide (oAβ) prevent induction of long-term potentiation (LTP) via the prior activation of GluN2B-containing NMDA receptors (NMDARs). However, the downstream Ca2+ -dependent signaling molecules that mediate aberrant metaplasticity are unknown. In this study, we show that oAβ promotes the activation of Ca2+ /calmodulin-dependent kinase II (CaMKII) via GluN2B-containing NMDARs...
June 12, 2018: Cell Reports
https://www.readbyqxmd.com/read/29893543/the-role-of-hydrophobicity-and-charge-of-amyloid-beta-oligomer-eliminating-d-peptides-in-the-interaction-with-amyloid-beta-monomers
#9
Tamar Ziehm, Alexander K Buell, Dieter Willbold
Inhibition of the self-assembly process of amyloid-beta and even more the removal of already existing toxic amyloid-beta assemblies represent promising therapeutic strategies against Alzheimer´s disease. To approach this aim, we selected a D-enantiomeric peptide by phage-display based on the interaction with amyloid-beta monomers. This lead compound was successfully optimized by peptide microarrays with respect to its affinity and specificity to the target resulting in D-peptides with both increased hydrophobicity and net charge...
June 12, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29889206/a11-positive-%C3%AE-amyloid-oligomer-preparation-and-assessment-using-dot-blotting-analysis
#10
Huang Chunhui, Xu Dilin, Zhang Ke, Shentu Jieyi, Yan Sicheng, Wu Dapeng, Wang Qinwen, Cui Wei
β-amyloid (Aβ) is a hydrophobic peptide with an intrinsic tendency to self-assemble into aggregates. Among various aggregates, Aβ oligomer is widely accepted as the leading neurotoxin in the progress of Alzheimer's disease (AD) and is considered to be the crucial event in the pathogenesis of AD. Therefore, Aβ oligomer inhibitors might prevent neurodegeneration and have the potential to be developed as disease-modifying treatments of AD. However, different formation protocols of Aβ oligomer might lead to oligomers with different characteristics...
May 22, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29887525/prion-protein-stabilizes-amyloid-%C3%AE-a%C3%AE-oligomers-and-enhances-a%C3%AE-neurotoxicity-in-a-drosophila-model-of-alzheimer-disease
#11
Nadine D Younan, Ko-Fan Chen, Ruth-Sarah Rose, Damian C Crowther, John H Viles
The cellular prion protein (PrPC ) can act as a cell-surface receptor for amyloid-β (Aβ) peptide; however, a role for PrPC in the pathogenesis of Alzheimer's disease (AD) is contested. Here, we expressed a range of Aβ isoforms and PrPC in the Drosophila brain. We found that co-expression of Aβ and PrPC significantly reduces the lifespan, disrupts circadian rhythms, and increases Aβ deposition in the fly brain. In contrast, under the same conditions, expression of Aβ or PrPC individually did not lead to these phenotypic changes...
June 10, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29886542/neurotoxic-ca-2-signaling-induced-by-amyloid-%C3%AE-oligomers-in-aged-hippocampal-neurons-in-vitro
#12
Lucía Núñez, María Calvo-Rodríguez, Erica Caballero, Mónica García-Durillo, Carlos Villalobos
Alzheimer's disease (AD), the most prevalent dementia linked to aging, involves neurotoxic effects of amyloid β species and dishomeostasis of intracellular Ca2+ . To investigate mechanisms of AD, the effects of soluble species of amyloid β oligomers (Aβo) prepared in medium devoid of glutamate receptor agonists can be tested on intracellular Ca2+ in long-term cultures of rat hippocampal neurons that reflect aging neurons. Furthermore, changes in expression of proteins involved in oligomer responses and AD can be tested in the same neurons using quantitative immunofluorescence...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29886536/noninvasive-structural-analysis-of-intermediate-species-during-fibrillation-an-application-of-small-angle-x-ray-scattering
#13
Annette Eva Langkilde, Fátima Herranz-Trillo, Pau Bernadó, Bente Vestergaard
Structural investigation of intermediately formed oligomers and pre-fibrillar species is of tremendous importance in order to elucidate the structural principles of fibrillation, and because intermediate species have been suggested as the pathogenic agents in several amyloid diseases. Structural investigations are however greatly complicated by the dynamic changes between structural states of very different sizes and life-times. Small angle X-ray scattering (SAXS) is an ideal method to handle this challenge...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29886533/preparation-of-amyloidogenic-aggregates-from-ef-hand-%C3%AE-parvalbumin-and-s100-proteins
#14
Javier Martínez, Joana S Cristóvão, Rosa Sánchez, Maria Gasset, Cláudio M Gomes
Proteins containing EF-hand helix-loop-helix-binding motifs play essential roles in calcium homeostasis and signaling pathways. These proteins have considerable structural and functional diversity by virtue of their cation-binding properties, and occur as either Ca2+ -bound or Ca2+ -free states with distinct aggregation propensities. That is the case among β-parvalbumins and S100 proteins, which under certain conditions undergo Ca2+ -dependent self-assembly reactions with the formation of oligomers, amyloid-type aggregates and fibrils...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29886524/preparation-of-a-well-defined-and-stable-%C3%AE-barrel-pore-forming-a%C3%AE-42-oligomer
#15
Montserrat Serra-Batiste, Martí Ninot-Pedrosa, Eduard Puig, Sonia Ciudad, Margarida Gairí, Natàlia Carulla
The formation of amyloid-β peptide (Aβ) oligomers at the cellular membrane is considered a crucial process that underlies neurotoxicity in Alzheimer's disease (AD). To obtain structural information on this type of oligomers, we were inspired by membrane protein approaches used to stabilize, characterize, and analyze the function of such proteins. Using these approaches, we developed conditions under which Aβ42, the Aβ variant most strongly linked to the aetiology of AD, assembles into an oligomer that inserts into lipid bilayers as a well-defined pore and adopts a specific structure with characteristics of a β-barrel arrangement...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29886523/preparation-of-pure-populations-of-amyloid-%C3%AE-protein-oligomers-of-defined-size
#16
Eric Y Hayden, Joseph L Conovaloff, Ashley Mason, Gal Bitan, David B Teplow
Protein and peptide oligomers are thought to play important roles in the pathogenesis of a number of neurodegenerative diseases. For this reason, considerable effort has been devoted to understanding the oligomerization process and to determining structure-activity relationships among the many types of oligomers that have been described. We discuss here a method for producing pure populations of amyloid β-protein (Aβ) of specific sizes using the most pathologic form of the peptide, Aβ42. This work was necessitated because Aβ oligomerization produces oligomers of many different sizes that are non-covalently associated, which means that dissociation or further assembly may occur...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29881722/highlights-in-bace1-inhibitors-for-alzheimer-s-disease-treatment
#17
REVIEW
Judite R M Coimbra, Daniela F F Marques, Salete J Baptista, Cláudia M F Pereira, Paula I Moreira, Teresa C P Dinis, Armanda E Santos, Jorge A R Salvador
Alzheimer's disease (AD) is a severe neurodegenerative disorder and the most common type of dementia in the elderly. The clinical symptoms of AD include a progressive loss of memory and impairment of cognitive functions interfering with daily life activities. The main neuropathological features consist in extracellular amyloid-β (Aβ) plaque deposition and intracellular Neurofibrillary tangles (NFTs) of hyperphosphorylated Tau. Understanding the pathophysiological mechanisms that underlie neurodegeneration in AD is essential for rational design of neuroprotective agents able to prevent disease progression...
2018: Frontiers in Chemistry
https://www.readbyqxmd.com/read/29872297/modeling-the-neuron-as-a-nanocommunication-system-to-identify-spatiotemporal-molecular-events-in-neurodegenerative-disease
#18
Arunima Banerjee, Janet L Paluh, Amitava Mukherjee, K Gaurav Kumar, Archisman Ghosh, Mrinal K Naskar
Aim: In tauopathies such as Alzheimer's disease (AD), molecular changes spanning multiple subcellular compartments of the neuron contribute to neurodegeneration and altered axonal signaling. Computational modeling of end-to-end linked events benefit mechanistic analysis and can be informative to understand disease progression and accelerate development of effective therapies. In the calcium-amyloid beta model of AD, calcium ions that are an important regulator of neuronal function undergo dysregulated homeostasis that disrupts cargo loading for neurotrophic signaling along axonal microtubules (MTs)...
2018: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/29871926/heme-and-hemoglobin-suppress-amyloid-%C3%AE-mediated-inflammatory-activation-of-mouse-astrocytes
#19
Sitara B Sankar, Rebecca K Donegan, Kajol J Shah, Amit R Reddi, Levi B Wood
Glial immune activity is a key feature of Alzheimer's disease (AD). Given that the blood factors heme and hemoglobin (Hb) are both elevated in AD tissues and have immunomodulatory roles, here we sought to interrogate their roles in modulating amyloid β (Aβ)-mediated inflammatory activation of astrocytes. We discovered that heme and Hb suppress immune activity of primary mouse astrocytes by reducing expression of several proinflammatory cytokines (e.g. RANTES) and the scavenger receptor CD36, and reducing internalization of Aβ1-42 by astrocytes...
June 5, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29866153/co-aggregation-of-pro-inflammatory-s100a9-with-%C3%AE-synuclein-in-parkinson-s-disease-ex-vivo-and-in-vitro-studies
#20
Istvan Horvath, Igor A Iashchishyn, Roman A Moskalenko, Chao Wang, Sebastian K T S Wärmländer, Cecilia Wallin, Astrid Gräslund, Gabor G Kovacs, Ludmilla A Morozova-Roche
BACKGROUND: Chronic neuroinflammation is a hallmark of Parkinson's disease (PD) pathophysiology, associated with increased levels of pro-inflammatory factors in PD brain tissues. The pro-inflammatory mediator and highly amyloidogenic protein S100A9 is involved in the amyloid-neuroinflammatory cascade in Alzheimer's disease. This is the first report on the co-aggregation of α-synuclein (α-syn) and S100A9 both in vitro and ex vivo in PD brain. METHODS: Single and sequential immunohistochemistry, immunofluorescence, scanning electron and atomic force (AFM) microscopies were used to analyze the ex vivo PD brain tissues for S100A9 and α-syn location and aggregation...
June 4, 2018: Journal of Neuroinflammation
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