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amyloid oligomer

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https://www.readbyqxmd.com/read/29453800/atomic-structures-of-corkscrew-forming-segments-of-sod1-reveal-varied-oligomer-conformations
#1
Smriti Sangwan, Michael R Sawaya, Kevin A Murray, MichaelP Hughes, David S Eisenberg
The aggregation cascade of disease-related amyloidogenic proteins, terminating in insoluble amyloid fibrils, involves intermediate oligomeric states. The structural and biochemical details of these oligomers have been largely unknown. Here we report crystal structures of variants of the cytotoxic oligomer-forming segment residues 28-38 of the ALS-linked protein, SOD1. The crystal structures reveal three different architectures: corkscrew oligomeric structure, non-twisting curved sheet structure and a steric zipper proto-filament structure...
February 17, 2018: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/29453790/amyloid-beta-1-40-is-associated-with-alterations-in-ng2-pericyte-population-ex-vivo-and-in-vitro
#2
Nina Schultz, Kristoffer Brännström, Elin Byman, Simon Moussaud, Henrietta M Nielsen, Anders Olofsson, Malin Wennström
The population of brain pericytes, a cell type important for vessel stability and blood brain barrier function, has recently been shown altered in patients with Alzheimer's disease (AD). The underlying reason for this alteration is not fully understood, but progressive accumulation of the AD characteristic peptide amyloid-beta (Aβ) has been suggested as a potential culprit. In the current study, we show reduced number of hippocampal NG2+ pericytes and an association between NG2+ pericyte numbers and Aβ1-40 levels in AD patients...
February 17, 2018: Aging Cell
https://www.readbyqxmd.com/read/29447116/amyloid-toxicity-in-alzheimer-s-disease
#3
REVIEW
Allison B Reiss, Hirra A Arain, Mark M Stecker, Nicolle M Siegart, Lora J Kasselman
A major feature of Alzheimer's disease (AD) pathology is the plaque composed of aggregated amyloid-β (Aβ) peptide. Although these plaques may have harmful properties, there is much evidence to implicate soluble oligomeric Aβ as the primary noxious form. Aβ oligomers can be generated both extracellularly and intracellularly. Aβ is toxic to neurons in a myriad of ways. It can cause pore formation resulting in the leakage of ions, disruption of cellular calcium balance, and loss of membrane potential. It can promote apoptosis, cause synaptic loss, and disrupt the cytoskeleton...
February 15, 2018: Reviews in the Neurosciences
https://www.readbyqxmd.com/read/29442807/inhibition-of-lysozyme-fibrillation-by-gold-nanorods-and-nanoparticles
#4
Hongli Liang, Bing Wang, Hailong Wang, Miao Yu, Lingna Zheng, Meng Wang, Aiping Zhang, Weiyue Feng
Amyloid fibrillation has been implicated in many neurodegenerations, dialysis-related amyloidosis, type II diabetes and more than 30 other amyloid-related diseases. Nanomaterials as potential inhibitors of amyloid fibrillation have attracted increasing interests. In the present study, the effects of gold nanorods (AuNRs) and nanoparticles (AuNPs) on amyloid fibrillation were investigated using hen egg white lysozyme (HEWL) as a model system. Our results indicated that AuNRs and AuNPs, especially AuNRs, present significant inhibitory effects on HEWL amyloid fibril formation during all the kinetic processes, from nucleation to elongation and equilibration stages...
May 1, 2018: Journal of Nanoscience and Nanotechnology
https://www.readbyqxmd.com/read/29441013/%C3%AE-synuclein-aggregated-with-tau-and-%C3%AE-amyloid-in-human-platelets-from-healthy-subjects-correlation-with-physical-exercise
#5
Simona Daniele, Deborah Pietrobono, Jonathan Fusi, Annalisa Lo Gerfo, Eugenio Cerri, Lucia Chico, Caterina Iofrida, Lucia Petrozzi, Filippo Baldacci, Chiara Giacomelli, Fabio Galetta, Gabriele Siciliano, Ubaldo Bonuccelli, Maria L Trincavelli, Ferdinando Franzoni, Claudia Martini
The loss of protein homeostasis that has been associated with aging leads to altered levels and conformational instability of proteins, which tend to form toxic aggregates. In particular, brain aging presents characteristic patterns of misfolded oligomers, primarily constituted of β-amyloid (Aβ), tau, and α-synuclein (α-syn), which can accumulate in neuronal membranes or extracellular compartments. Such aging-related proteins can also reach peripheral compartments, thus suggesting the possibility to monitor their accumulation in more accessible fluids...
2018: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/29441010/an-aged-canid-with-behavioral-deficits-exhibits-blood-and-cerebrospinal-fluid-amyloid-beta-oligomers
#6
Clare Rusbridge, Francisco J Salguero, Monique Antoinette David, Kiterie M E Faller, Jose T Bras, Rita J Guerreiro, Angela C Richard-Londt, Duncan Grainger, Elizabeth Head, Sebastian G P Brandner, Brian Summers, John Hardy, Mourad Tayebi
Many of the molecular and pathological features associated with human Alzheimer disease (AD) are mirrored in the naturally occurring age-associated neuropathology in the canine species. In aged dogs with declining learned behavior and memory the severity of cognitive dysfunction parallels the progressive build up and location of Aβ in the brain. The main aim of this work was to study the biological behavior of soluble oligomers isolated from an aged dog with cognitive dysfunction through investigating their interaction with a human cell line and synthetic Aβ peptides...
2018: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/29439327/stabilized-low-n-amyloid-%C3%AE-oligomers-induce-robust-novel-object-recognition-deficits-associated-with-inflammatory-synaptic-and-gabaergic-dysfunction-in-the-rat
#7
William Watremez, Joshua Jackson, Bushra Almari, Samantha L McLean, Ben Grayson, Joanna C Neill, Nicolas Fischer, Ahmad Allouche, Violette Koziel, Thierry Pillot, Michael K Harte
BACKGROUND: With current treatments for Alzheimer's disease (AD) only providing temporary symptomatic benefits, disease modifying drugs are urgently required. This approach relies on improved understanding of the early pathophysiology of AD. A new hypothesis has emerged, in which early memory loss is considered a synapse failure caused by soluble amyloid-β oligomers (Aβo). These small soluble Aβo, which precede the formation of larger fibrillar assemblies, may be the main cause of early AD pathologies...
2018: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/29435980/the-diabetes-drug-liraglutide-reverses-cognitive-impairment-in-mice-and-attenuates-insulin-receptor-and-synaptic-pathology-in-a-non-human-primate-model-of-alzheimer-s-disease
#8
Andre F Batista, Leticia Forny-Germano, Julia R Clarke, Natalia M Lyra E Silva, Jordano Brito-Moreira, Susan E Boehnke, Andrew Winterborn, Brian C Coe, Ann Lablans, Juliana F Vital, Suelen A Marques, Ana M B Martinez, Matthias Gralle, Christian Holscher, William L Klein, Jean-Christophe Houzel, Sergio T Ferreira, Douglas P Munoz, Fernanda G De Felice
Alzheimer's disease (AD) is a devastating neurological disorder that still lacks an effective treatment, and this has stimulated an intense pursuit of disease-modifying therapeutics. Given the increasingly recognized link between AD and defective brain insulin signaling, we investigated the actions of liraglutide, a glucagon-like peptide-1 (GLP-1) analog marketed for treatment of type 2 diabetes, in experimental models of AD. Insulin receptor pathology is an important feature of AD brains that impairs the neuroprotective actions of central insulin signaling...
February 12, 2018: Journal of Pathology
https://www.readbyqxmd.com/read/29432676/genistein-a-dual-inhibitor-of-both-a%C3%AE-and-hiapp-peptides
#9
Baiping Ren, Yonglan Liu, Yanxian Zhang, Yongqing Cai, Xiong Gong, Yung Chang, Lijian Xu, Jie Zheng
Abnormal misfolding and aggregation of amyloid peptides into amyloid fibrils are a common and critical pathological event in many neurodegenerative diseases. Most of inhibitors or drugs have been developed to prevent amyloid aggregation of a specific peptide, exhibiting sequence-dependent inhibition mechanisms. It is more challenging to develop or discover inhibitors capable of preventing the aggregation of two or more different amyloid peptides. Genistein, a major phytoestrogen in soybean, has been widely used as anti-inflammation and cerebrovascular drugs due to their anti-oxidation and anti-acetylcholinesterase effects...
February 12, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29429575/mechanistic-analyses-of-the-suppression-of-amyloid-%C3%AE-42-aggregation-by-apomorphine
#10
Mizuho Hanaki, Kazuma Murakami, Sumie Katayama, Ken-Ichi Akagi, Kazuhiro Irie
(R)-Apomorphine (1) has the potential to reduce the accumulation of amyloid β-protein (Aβ42), a causative agent of Alzheimer's disease (AD). Although the inhibition of Aβ42 aggregation by 1 is ascribable to the antioxidative effect of its phenol moiety, its inhibitory mechanism at the molecular level remains to be fully elucidated. LC-MS and UV analyses revealed that 1 is autoxidized during incubation to produce an unstable o-quinone form (2), which formed a Michael adduct with Lys 16 and 28 of Aβ42. A further autoxidized form of 1 (3) with o-quinone and phenanthrene moieties suppressed Aβ42 aggregation comparable to 1, whereas treating 1 with a reductant, tris(2-carboxyethyl)phosphine diminished its inhibitory activity...
February 2, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29428499/atomistic-level-study-of-the-interactions-between-hiapp-protofibrils-and-membranes-influence-of-ph-and-lipid-composition
#11
Zhenyu Qian, Yu Zou, Qingwen Zhang, Peijie Chen, Buyong Ma, Guanghong Wei, Ruth Nussinov
The pathology of type 2 diabetes mellitus is associated with the aggregation of human islet amyloid polypeptide (hIAPP) and aggregation-mediated membrane disruption. The interactions of hIAPP aggregates with lipid membrane, as well as the effects of pH and lipid composition at the atomic level, remain elusive. Herein, using molecular dynamics simulations, we investigate the interactions of hIAPP protofibrillar oligomers with lipids, and the membrane perturbation that they induce, when they are partially inserted in an anionic dipalmitoyl-phosphatidylglycerol (DPPG) membrane or a mixed dipalmitoyl-phosphatidylcholine (DPPC)/DPPG (7:3) lipid bilayer under acidic/neutral pH conditions...
February 8, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29421570/design-synthesis-and-pharmacological-evaluation-of-n-benzyl-piperidinyl-aryl-acylhydrazone-derivatives-as-donepezil-hybrids-discovery-of-novel-multi-target-anti-alzheimer-prototype-drug-candidates
#12
Flávia Pereira Dias Viegas, Matheus de Freitas Silva, Miguel Divino da Rocha, Maísa Rosa Castelli, Mariana Máximo Riquiel, Rafael Pereira Machado, Sarah Macedo Vaz, Laís Medeiros Simões de Lima, Karla Cristine Mancini, Patrícia Cruz Marques de Oliveira, Élida Parreira Morais, Vanessa Silva Gontijo, Fernanda Motta R da Silva, Dora D'Alincourt da Fonseca Peçanha, Newton Gonçalves Castro, Gilda A Neves, Alexandre Giusti-Paiva, Fabiana Cardoso Vilela, Lidiane Orlandi, Ihosvany Camps, Márcia Paranho Veloso, Luis Felipe Leomil Coelho, Marisa Ionta, Guilherme Álvaro Ferreira-Silva, Rodrigo Machado Pereira, Laurent E Dardenne, Isabella Alvim Guedes, Wellerson de Oliveira Carneiro Junior, Paula Maria Quaglio Bellozi, Antônio Carlos Pinheiro de Oliveira, Fábio Furlan Ferreira, Letizia Pruccoli, Andrea Tarozzi, Claudio Viegas
A new series of sixteen multifunctional N-benzyl-piperidine-aryl-acylhydrazones hybrid derivatives was synthesized and evaluated for multi-target activities related to Alzheimer's disease (AD). The molecular hybridization approach was based on the combination, in a single molecule, of the pharmacophoric N-benzyl-piperidine subunit of donepezil, the substituted hydroxy-piperidine fragment of the AChE inhibitor LASSBio-767, and an acylhydrazone linker, a privileged structure present in a number of synthetic aryl- and aryl-acylhydrazone derivatives with significant AChE and anti-inflammatory activities...
January 31, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29414699/propagation-of-an-a%C3%AE-dodecamer-strain-involves-a-three-step-mechanism-and-a-key-intermediate
#13
Dexter N Dean, Pratip Rana, Ryan P Campbell, Preetam Ghosh, Vijayaraghavan Rangachari
Proteinaceous deposits composed of fibrillar amyloid-β (Aβ) are the primary neuropathological hallmarks in Alzheimer disease (AD) brains. The nucleation-dependent aggregation of Aβ is a stochastic process with frequently observed heterogeneity in aggregate size, structure, and conformation that manifests in fibril polymorphism. Emerging evidence indicates that polymorphic variations in Aβ fibrils contribute to phenotypic diversity and the rate of disease progression in AD. We recently demonstrated that a dodecamer strain derived from synthetic Aβ42 propagates to morphologically distinct fibrils and selectively induces cerebral amyloid angiopathy phenotype in transgenic mice...
February 6, 2018: Biophysical Journal
https://www.readbyqxmd.com/read/29414379/prion-like-seeding-and-nucleation-of-intracellular-amyloid-%C3%AE
#14
Tomas T Olsson, Oxana Klementieva, Gunnar K Gouras
Alzheimer's disease (AD) brain tissue can act as a seed to accelerate aggregation of amyloid-β (Aβ) into plaques in AD transgenic mice. Aβ seeds have been hypothesized to accelerate plaque formation in a prion-like manner of templated seeding and intercellular propagation. However, the structure(s) and location(s) of the Aβ seeds remain unknown. Moreover, in contrast to tau and α-synuclein, an in vitro system with prion-like Aβ has not been reported. Here we treat human APP expressing N2a cells with AD transgenic mouse brain extracts to induce inclusions of Aβ in a subset of cells...
January 29, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29413525/synaptotoxic-signaling-by-amyloid-beta-oligomers-in-alzheimer-s-disease-through-prion-protein-and-mglur5
#15
A Harrison Brody, Stephen M Strittmatter
Alzheimer's disease (AD) represents an impending global health crisis, yet the complexity of AD pathophysiology has so far precluded the development of any interventions to successfully slow or halt AD progression. It is clear that accumulation of Amyloid-beta (Aβ) peptide triggers progressive synapse loss to cause AD symptoms. Once initiated by Aβ, disease progression is complicated and accelerated by inflammation and by tau pathology. The recognition that Aβ peptide assumes multiple distinct states and that soluble oligomeric species (Aβo) are critical for synaptic damage is central to molecular understanding of AD...
2018: Advances in Pharmacology
https://www.readbyqxmd.com/read/29412673/what-is-responsible-for-atypical-dependence-of-the-rate-of-amyloid-formation-on-protein-concentration-fibril-catalyzed-initiation-of-new-fibrils-or-competition-with-oligomers
#16
Alexei V Finkelstein, Nikita V Dovidchenko, Oxana Valerianovna Galzitskaya
An abnormal dependence of the rate of amyloid formation on protein concentration has been recently observed by Meisl et al. for Aβ40 peptides associated with Alzheimer's disease. To explain this effect, Meisl et al. proposed a novel mechanism of fibril growth: the fibril-catalyzed initiation of fibril formation. In this paper we offer an alternative explanation of the observed anomalous kinetics: formation of metastable oligomers competing with fibril formation by decreasing the concentration of the fibril-forming free monomers...
February 7, 2018: Journal of Physical Chemistry Letters
https://www.readbyqxmd.com/read/29410161/trace-amounts-of-pyroglutaminated-a%C3%AE-3-42-enhance-aggregation-of-a%C3%AE-1-42-on-neuronal-membranes-at-physiological-concentrations-fcs-analysis-of-cell-surface
#17
Yoshiaki Yano, An Takeno, Katsumi Matsuzaki
Minor species of amyloid β-peptide (Aβ), such as Aβ-(1-43) and pyroglutaminated Aβ-(3-42) (Aβ-(3pE-42)), have been suggested to be involved in the initiation of the Aβ aggregation process, which is closely associated with the etiology of Alzheimer's disease. They can play important roles in aggregation not only in the aqueous phase but also on neuroral membranes; however, the latter behaviors remain mostly unexplored. Here, initial aggregation processes of Aβ on living cells were monitored at physiological nanomolar concentrations by fluorescence correlation spectroscopy...
February 1, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29409811/serum-albumin-s-protective-inhibition-of-amyloid-%C3%AE-fibre-formation-is-suppressed-by-cholesterol-fatty-acids-and-warfarin
#18
David C Bode, Helen F Stanyon, Trisha Hirani, Mark D Baker, Jon Nield, John H Viles
Central to Alzheimer's disease (AD) pathology is the assembly of monomeric amyloid-β peptide (Aβ) into oligomers and fibres. The most abundant protein in the blood plasma and cerebrospinal fluid (CSF) is human serum albumin (HSA). Albumin can bind to Aβ and is capable of inhibiting the fibrillisation of Aβ at physiological (μM) concentrations. The ability of albumin to bind Aβ has recently been exploited in a phase-II clinical trial, which showed a reduction in cognitive decline in Alzheimer's disease patients undergoing albumin plasma-exchange...
February 1, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29409004/acceleration-of-nucleation-of-prion-protein-during-continuous-ultrasonication
#19
Kei-Ichi Yamaguchi, Ryo P Honda, Abdelazim Elsayed Elhelaly, Kazuo Kuwata
Although pulsatile irradiation of ultrasonication is frequently used for generating amyloid fibrils in vitro, the potential for inducing amyloid fibrillation of proteins during continuous ultrasonication is unknown. In this study, we implemented a continuous irradiation system and measured far-ultraviolet circular dichroism in a real-time manner. During the continuous ultrasonication, the conformation of full-length mouse prion protein (mPrP) was rapidly altered without a lag time, and electron microscopy revealed that distorted fibrils, β-oligomers, and amorphous aggregates were formed at pH 2...
February 2, 2018: Journal of Biochemistry
https://www.readbyqxmd.com/read/29394903/impact-of-amyloid-beta-changes-on-cognitive-outcomes-in-alzheimer-s-disease-analysis-of-clinical-trials-using-a-quantitative-systems-pharmacology-model
#20
Hugo Geerts, Athan Spiros, Patrick Roberts
BACKGROUND: Despite a tremendous amount of information on the role of amyloid in Alzheimer's disease (AD), almost all clinical trials testing this hypothesis have failed to generate clinically relevant cognitive effects. METHODS: We present an advanced mechanism-based and biophysically realistic quantitative systems pharmacology computer model of an Alzheimer-type neuronal cortical network that has been calibrated with Alzheimer Disease Assessment Scale, cognitive subscale (ADAS-Cog) readouts from historical clinical trials and simulated the differential impact of amyloid-beta (Aβ40 and Aβ42) oligomers on glutamate and nicotinic neurotransmission...
February 2, 2018: Alzheimer's Research & Therapy
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