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Amyloid oligomers

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https://www.readbyqxmd.com/read/28729427/sialylated-glycosylphosphatidylinositols-suppress-the-production-of-toxic-amyloid-%C3%AE-oligomers
#1
William Nolan, Harriet McHale-Owen, Clive Bate
The production of amyloid-β (Aβ) is a key factor driving pathogenesis in Alzheimer's disease (AD). Increasing concentrations of soluble Aβ oligomers within the brain lead to synapse degeneration and the progressive dementia characteristic of AD. Since Aβ exists in both disease-relevant (toxic) and non-toxic forms, the factors that affected the release of toxic Aβ were studied in a cell model. 7PA2 cells expressing the human amyloid precursor protein released Aβ oligomers that caused synapse damage when incubated with cultured neurons...
July 20, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28728224/-antagonism-of-lovastatin-on-oxidative-stress-and-apoptosis-in-primary-rat-hippocampal-neurons-induced-by-%C3%AE-amyloid-peptide
#2
L C Tan, L Zhao, X H Liu, C M Deng, Z Z Guan
Objective: To investigate the effect of lovastatin on oxidative stress and apoptosis in neurons induced by β-amyloid peptide (Aβ). Methods: Primary culture of rat hippocampal neuron was treated with Aβ oligomers alone or combined with lovastatin. The levels of OH(-), H(2)O(2), O(2)·(-), malondialdehyde, superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities were measured by biochemical methods and protein expression of caspase-3 and bcl-2 was detected by Western blot. Results: As compared with the control group, treatment of 0...
July 8, 2017: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
https://www.readbyqxmd.com/read/28727426/fully-atomistic-a%C3%AE-40-and-a%C3%AE-42-oligomers-in-water-observation-of-pore-like-conformations
#3
Matthew John Voelker, Bogdan Barz, Brigita Urbanc
Oligomers formed by amyloid β-protein (Aβ) are central to Alzheimer's disease (AD) pathology, yet their structure remains elusive. Of the two predominant Aβ alloforms, Aβ40 and Aβ42, the latter is more strongly associated with AD. Here, we structurally characterized Aβ40 and Aβ42 monomers through pentamers which were converted from previously derived coarse-grained (DMD4B-HYDRA) simulations into all-atom conformations and subjected to explicit-solvent MD. Free energy landscapes revealed that structural differences between Aβ40 and Aβ42 conformations increase with oligomer order up to trimers...
July 20, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28720893/nanoplasmonic-fiber-tip-probe-detects-significant-reduction-of-intracellular-alzheimer-s-disease-related-oligomers-by-curcumin
#4
Feng Liang, Yu Wan, Diane Schaak, Joseph Ward, Xunuo Shen, Rudolph E Tanzi, Can Zhang, Qimin Quan
Considerable evidence shows critical roles of intracellular pathogenic events of Alzheimer's disease (AD). In particular, intracellular amyloid-β accumulation and oligomerization are early AD pathologic processes, which may lead to changes in inflammatory molecules and other AD-related pathological components. Curcumin and its analogs have been identified as potential drug candidates for AD. However, the effects of curcumin on intracellular AD pathologic processes remain largely unknown. Here we utilized a recently developed nanoplasmonic fiber tip probe (nFTP) technology and investigated whether curcumin leads to intracellular AD pathologic changes...
July 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28711713/surprisingly-high-stability-of-the-a%C3%AE-oligomer-eliminating-all-d-enantiomeric-peptide-d3-in-media-simulating-the-route-of-orally-administered-drugs
#5
Anne Elfgen, Beatrix Santiago-Schübel, Lothar Gremer, Janine Kutzsche, Dieter Willbold
The aggregation of the amyloid β protein (Aβ) plays an important role in the pathology of Alzheimer's disease. Previously, we have developed the all-d-enantiomeric peptide D3, which is able to eliminate neurotoxic Aβ oligomers in vitro and improve cognition in a transgenic Alzheimer's disease mouse model in vivo even after oral administration. d-Peptides are expected to be more resistant against enzymatic proteolysis compared to their l-enantiomeric equivalents, and indeed, a pharmacokinetic study with tritiated D3 revealed the oral bioavailability to be about 58%...
July 12, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28709498/targeting-fyn-kinase-in-alzheimer-s-disease
#6
REVIEW
Haakon B Nygaard
The past decade has brought tremendous progress in unraveling the pathophysiology of Alzheimer's disease (AD). While increasingly sophisticated immunotherapy targeting soluble and aggregated brain amyloid-beta (Aβ) continues to dominate clinical research in AD, a deeper understanding of Aβ physiology has led to the recognition of distinct neuronal signaling pathways linking Aβ to synaptotoxicity and neurodegeneration and to new targets for therapeutic intervention. Identifying specific signaling pathways involving Aβ has allowed for the development of more precise therapeutic interventions targeting the most relevant molecular mechanisms leading to AD...
June 13, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/28702592/inhibition-of-gnnqqny-prion-peptide-aggregation-by-trehalose-a-mechanistic-view
#7
Nidhi Katyal, Shashank Deep
Deposition of amyloid fibrils is the seminal event in the pathogenesis of numerous neurodegenerative diseases. The formation of this amyloid assembly is the manifestation of a cascade of structural transitions including toxic oligomer formation in the early stages of aggregation. Thus a viable therapeutic strategy involves the use of small molecular ligands to interfere with this assembly. In this perspective, we have explored the kinetics of aggregate formation of the fibril forming GNNQQNY peptide fragment from the yeast prion protein SUP35 using multiple all atom MD simulations with explicit solvent and provided mechanistic insights into the way trehalose, an experimentally known aggregation inhibitor, modulates the aggregation pathway...
July 12, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28702523/implications-of-peptide-assemblies-in-amyloid-diseases
#8
REVIEW
Pu Chun Ke, Marc-Antonie Sani, Feng Ding, Aleksandr Kakinen, Ibrahim Javed, Frances Separovic, Thomas P Davis, Raffaele Mezzenga
Neurodegenerative disorders and type 2 diabetes are global epidemics compromising the quality of life of millions worldwide, with profound social and economic implications. Despite the significant differences in pathology - much of which are poorly understood - these diseases are commonly characterized by the presence of cross-β amyloid fibrils as well as the loss of neuronal or pancreatic β-cells. In this review, we document research progress on the molecular and mesoscopic self-assembly of amyloid-beta, alpha synuclein, human islet amyloid polypeptide and prions, the peptides and proteins associated with Alzheimer's, Parkinson's, type 2 diabetes and prion diseases...
July 12, 2017: Chemical Society Reviews
https://www.readbyqxmd.com/read/28699522/targeting-human-astrocytes-calcium-sensing-receptors-for-treatment-of-alzheimer-s-disease
#9
Anna Chiarini, Ubaldo Armato, James F Whitfield, Ilaria Dal Pra
Understanding the pathophysiology of Alzheimer's disease (AD) in the principal human neural cells is necessary for finding therapeutics for this illness. To help do this, we have been using freshly cultured functionally normal cerebral cortical adult human astrocytes (NAHAs) and postnatal neurons. The findings show that amyloid-β oligomers (Aβ-os) binding to calcium-sensing receptors (CaSRs) on NAHAs and neuron surfaces trigger signals capable of driving AD pathogenesis. This Aβ•CaSR signalling shifts the amyloid precursor protein (APP) from its α-secretase shedding producing neurotrophic/neuroprotective soluble (s)APPα to its β-secretase cleaving engendering AD-driving Aβ42/Aβ42-os peptides...
July 10, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28698968/inhibition-of-poly-adp-ribose-polymerase-1-enhances-gene-expression-of-selected-sirtuins-and-app-cleaving-enzymes-in-amyloid-beta-cytotoxicity
#10
Przemysław L Wencel, Walter J Lukiw, Joanna B Strosznajder, Robert Piotr Strosznajder
Poly(ADP-ribose) polymerases (PARPs) and sirtuins (SIRTs) are involved in the regulation of cell metabolism, transcription, and DNA repair. Alterations of these enzymes may play a crucial role in Alzheimer's disease (AD). Our previous results indicated that amyloid beta (Aβ) peptides and inflammation led to activation of PARP1 and cell death. This study focused on a role of PARP1 in the regulation of gene expression for SIRTs and beta-amyloid precursor protein (βAPP) cleaving enzymes under Aβ42 oligomers (AβO) toxicity in pheochromocytoma cells (PC12) in culture...
July 12, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28696431/synaptic-activity-protects-against-ad-and-ftd-like-pathology-via-autophagic-lysosomal-degradation
#11
Y Akwa, E Gondard, A Mann, E Capetillo-Zarate, E Alberdi, C Matute, S Marty, T Vaccari, A M Lozano, E E Baulieu, D Tampellini
Changes in synaptic excitability and reduced brain metabolism are among the earliest detectable alterations associated with the development of Alzheimer's disease (AD). Stimulation of synaptic activity has been shown to be protective in models of AD beta-amyloidosis. Remarkably, deep brain stimulation (DBS) provides beneficial effects in AD patients, and represents an important therapeutic approach against AD and other forms of dementia. While several studies have explored the effect of synaptic activation on beta-amyloid, little is known about Tau protein...
July 11, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28696204/ltp-and-memory-impairment-caused-by-extracellular-a%C3%AE-and-tau-oligomers-is-app-dependent
#12
Daniela Puzzo, Roberto Piacentini, Mauro Fa', Walter Gulisano, Domenica D Li Puma, Agnes Staniszewski, Hong Zhang, Maria Rosaria Tropea, Sara Cocco, Agostino Palmeri, Paul Fraser, Luciano D'Adamio, Claudio Grassi, Ottavio Arancio
The concurrent application of subtoxic doses of soluble oligomeric forms of human amyloid-beta (oAβ) and Tau (oTau) proteins impairs memory and its electrophysiological surrogate long-term potentiation (LTP), effects that may be mediated by intra-neuronal oligomers uptake. Intrigued by these findings, we investigated whether oAβ and oTau share a common mechanism when they impair memory and LTP in mice. We found that as already shown for oAβ, also oTau can bind to amyloid precursor protein (APP). Moreover, efficient intra-neuronal uptake of oAβ and oTau requires expression of APP...
July 11, 2017: ELife
https://www.readbyqxmd.com/read/28691424/an-animal-model-of-the-procognitive-properties-of-cysteine-protease-inhibitor-and-immunomodulatory-peptides-based-on-colostrum
#13
Bartłomiej Stańczykiewicz, Marta Jakubik-Witkowska, Antoni Polanowski, Tadeusz Trziszka, Joanna Rymaszewska
BACKGROUND: The positive effect of human cystatin C on the development of Alzheimer's disease has been reported, as it inhibits the formation of β-amyloid oligomers and amyloidogenesis. Cystatin C has been found to have a neuroprotective effect through inhibiting cysteine proteases, inducing autophagy and neurogenesis. There is a growing interest in the procognitive properties of colostrum-based specimens, which could delay dementia and ameliorate memory deterioration. OBJECTIVES: The aim of the study was to evaluate the influence of Ovocystatin and a Coloco peptide complex on the cognitive functions in reference to Colostrinin, using a model of young and old rats...
June 27, 2017: Advances in Clinical and Experimental Medicine: Official Organ Wroclaw Medical University
https://www.readbyqxmd.com/read/28685098/designed-%C3%AE-sheet-peptides-suppress-amyloid-formation-in-staphylococcus-aureus-biofilms
#14
Alissa Bleem, Robyn Francisco, James D Bryers, Valerie Daggett
Nosocomial infections affect hundreds of millions of patients worldwide each year, and ~60% of these infections are associated with biofilm formation on an implanted medical device. Biofilms are dense communities of microorganisms in which cells associate with surfaces and each other using a self-produced extracellular matrix composed of proteins, polysaccharides, and genetic material. Proteins in the extracellular matrix take on a variety of forms, but here we focus on functional amyloid structures. Amyloids have long been associated with protein misfolding and neurodegenerative diseases, but recent research has demonstrated that numerous bacterial species utilize the amyloid fold to fortify the biofilm matrix and resist disassembly...
2017: NPJ Biofilms and Microbiomes
https://www.readbyqxmd.com/read/28683776/trpa1-channels-promote-astrocytic-ca-2-hyperactivity-and-synaptic-dysfunction-mediated-by-oligomeric-forms-of-amyloid-%C3%AE-peptide
#15
Anthony Bosson, Adrien Paumier, Sylvie Boisseau, Muriel Jacquier-Sarlin, Alain Buisson, Mireille Albrieux
BACKGROUND: Excessive synaptic loss is thought to be one of the earliest events in Alzheimer's disease (AD). However, the key mechanisms that maintain plasticity of synapses during adulthood or initiate synapse dysfunction in AD remain unknown. Recent studies suggest that astrocytes contribute to functional changes observed during synaptic plasticity and play a major role in synaptic dysfunction but astrocytes behavior and involvement in early phases of AD remained largely undefined. METHODS: We measure astrocytic calcium activity in mouse CA1 hippocampus stratum radiatum in both the global astrocytic population and at a single cell level, focusing in the highly compartmentalized astrocytic arbor...
July 6, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28683598/mechanistic-comparison-of-current-pharmacological-treatments-and-novel-phytochemicals-to-target-amyloid-peptides-in-alzheimer-s-and-neurodegenerative-diseases
#16
Neelima Ayyalasomayajula, Challa Suresh
The formation of β amyloid plaques is one of the pathological hallmarks of Alzheimer's disease (AD). The process of accumulation of extracellular deposits of amyloid plaques occurs by the abnormal proteolysis of amyloid precursor protein, resulting in the formation of β amyloid peptides which further aggregates and results in the formation of oligomers, protofibrils, fibrils, and plaques. The complexity in understanding the aggregation process has provided avenues for identifying potential targets against amyloid toxicity in the treatment of AD...
July 6, 2017: Nutritional Neuroscience
https://www.readbyqxmd.com/read/28683555/x-ray-crystallographic-structure-of-a-compact-dodecamer-from-a-peptide-derived-from-a%C3%AE-16-36
#17
Patrick J Salveson, Ryan K Spencer, Adam G Kreutzer, James S Nowick
The assembly of the β-amyloid peptide, Aβ, into soluble oligomers is associated with neurodegeneration in Alzheimer's disease. The Aβ oligomers are thought to be composed of β-hairpins. Here, the effect of shifting the residue pairing of the β-hairpins on the structures of the oligomers that form is explored through X-ray crystallography. Three residue pairings were investigated using constrained macrocyclic β-hairpins in which Aβ30-36 is juxtaposed with Aβ17-23, Aβ16-22, and Aβ15-21. The Aβ16-22-Aβ30-36 pairing forms a compact ball-shaped dodecamer composed of fused triangular trimers...
July 7, 2017: Organic Letters
https://www.readbyqxmd.com/read/28683325/silent-allosteric-modulation-of-mglur5-maintains-glutamate-signaling-while-rescuing-alzheimer-s-mouse-phenotypes
#18
Laura T Haas, Santiago V Salazar, Levi M Smith, Helen R Zhao, Timothy O Cox, Charlotte S Herber, Andrew P Degnan, Anand Balakrishnan, John E Macor, Charles F Albright, Stephen M Strittmatter
Metabotropic glutamate receptor 5 (mGluR5) has been implicated in Alzheimer's disease (AD) pathology. We sought to understand whether mGluR5's role in AD requires glutamate signaling. We used a potent mGluR5 silent allosteric modulator (SAM, BMS-984923) to separate its well-known physiological role in glutamate signaling from a pathological role in mediating amyloid-β oligomer (Aβo) action. Binding of the SAM to mGluR5 does not change glutamate signaling but strongly reduces mGluR5 interaction with cellular prion protein (PrP(C)) bound to Aβo...
July 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/28682473/suppression-of-oligomer-formation-and-formation-of-non-toxic-fibrils-upon-addition-of-mirror-image-a%C3%AE-42-to-the-natural-l-enantiomer
#19
Subrata Dutta, Alejandro R Foley, Christopher J A Warner, Xiaolin Zhang, Marco Rolandi, Benjamin Abrams, Jevgenij A Raskatov
Racemates often have lower solubility than enantiopure compounds, and the mixing of enantiomers can enhance the aggregation propensity of peptides. Amyloid beta (Aβ) 42 is an aggregation-prone peptide that is believed to play a key role in Alzheimer's disease. Soluble Aβ42 aggregation intermediates (oligomers) have emerged as being particularly neurotoxic. We hypothesized that the addition of mirror-image d-Aβ42 should reduce the concentration of toxic oligomers formed from natural l-Aβ42. We synthesized l- and D-Aβ42 and found their equimolar mixing to lead to accelerated fibril formation...
July 6, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28672144/zn-ii-pramlintide-stability-binding-sites-and-unexpected-aggregation
#20
D Łoboda, M Rowińska-Żyrek
Pramlintide is an antidiabetic drug which mimics amylin - a small peptide co-secreted from pancreatic β-cells together with insulin, one of the hallmarks of type 2 diabetes. In the course of the disease, amylin misfolds into small oligomers or to an aggregated β-sheet amyloid fiber. The misfolding mechanism is not yet quite understood, but it is clear that zinc ions play an important role in the process. This work sheds new light on the role of zinc and pramlintide in the course of the disease, giving a detailed description of the Zn(II)-pramlintide complex, in which the metal ion binds to the imidazole of His18 and the amine group of Lys1, imposing a bend in the peptide between these residues...
September 2017: Journal of Inorganic Biochemistry
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