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Amyloid oligomers

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https://www.readbyqxmd.com/read/28102321/the-chaperonin-cct-inhibits-assembly-of-%C3%AE-synuclein-amyloid-fibrils-by-a-specific-conformation-dependent-interaction
#1
Begoña Sot, Alejandra Rubio-Muñoz, Ahudrey Leal-Quintero, Javier Martínez-Sabando, Miguel Marcilla, Cintia Roodveldt, José M Valpuesta
The eukaryotic chaperonin CCT (chaperonin containing TCP-1) uses cavities built into its double-ring structure to encapsulate and to assist folding of a large subset of proteins. CCT can inhibit amyloid fibre assembly and toxicity of the polyQ extended mutant of huntingtin, the protein responsible for Huntington's disease. This raises the possibility that CCT modulates other amyloidopathies, a still-unaddressed question. We show here that CCT inhibits amyloid fibre assembly of α-synuclein A53T, one of the mutants responsible for Parkinson's disease...
January 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28102308/corrigendum-pre-amyloid-oligomers-budding-a-metastatic-mechanism-of-proteotoxicity
#2
Fabrizio Bernini, Daniele Malferrari, Marcello Pignataro, Carlo Augusto Bortolotti, Giulia Di Rocco, Lidia Lancellotti, Maria Franca Brigatti, Rakez Kayed, Marco Borsari, Federica Del Monte, Elena Castellini
No abstract text is available yet for this article.
January 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28098204/strain-specific-fibril-propagation-by-an-a%C3%AE-dodecamer
#3
Dexter N Dean, Pradipta K Das, Pratip Rana, Franklin Burg, Yona Levites, Sarah E Morgan, Preetam Ghosh, Vijayaraghavan Rangachari
Low molecular weight oligomers of amyloid-β (Aβ) have emerged as the primary toxic agents in the etiology of Alzheimer disease (AD). Polymorphism observed within the aggregation end products of fibrils are known to arise due to microstructural differences among the oligomers. Diversity in aggregate morphology correlates with the differences in AD, cementing the idea that conformational strains of oligomers could be significant in phenotypic outcomes. Therefore, it is imperative to determine the ability of strains to faithfully propagate their structure...
January 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28094495/bacoside-a-an-indian-traditional-medicine-substance-inhibits-beta-amyloid-cytotoxicity-fibrillation-and-membrane-interactions
#4
Ravit Malishev, Shira Shaham-Niv, Sukhendu Nandi, Sofiya Kolusheva, Ehud Gazit, Raz Jelinek
Bacoside-A, a family of compounds extracted from the Bacopa monniera plant, is a folk-medicinal substance believed to exhibit therapeutic properties, particularly enhancing cognitive functions and improving memory. We show that bacoside-A exerted significant inhibitory effects upon cytotoxicity, fibrillation, and particularly membrane interactions of amyloid-beta (1-42) (Aβ42), the peptide playing a prominent role in Alzeheimer's disease progression and toxicity. Specifically, pre-incubation of bacoside-A with Aβ42 significantly reduced cell toxicity and inhibited fibril formation both in buffer solution and, more significantly, in the presence of membrane vesicles...
January 17, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28093972/conformation-as-the-therapeutic-target-for-neurodegenerative-diseases
#5
Rajaraman Krishnan, Franz Hefti, Haim Tsubery, Michal Lulu, Ming Proschitsky, Richard Fisher
Therapeutic strategies that target pathways of protein misfolding and the toxicity of intermediates along these pathways are mainly at discovery and early development stages, with the exception of monoclonal antibodies that have mainly failed to produce convincing clinical benefits in late stage trials. The clinical failures represent potentially critical lessons for future neurodegenerative disease drug development. More effective drugs may be achieved by pursuing the following two strategies. First, conformational targeting of aggregates of misfolded proteins, rather than less specific binding that includes monomer subunits, which vastly outnumber the toxic targets...
January 16, 2017: Current Alzheimer Research
https://www.readbyqxmd.com/read/28088900/synaptic-plasticity-dementia-and-alzheimer-disease
#6
Pietro Giusti, Stephen D Skaper, Laura Facci, Morena Zusso
Neuroplasticity is not only shaped by learning and memory but is also a mediator of responses to neuron attrition and injury (compensatory plasticity). As an ongoing process it reacts to neuronal cell activity and injury, death, and genesis, which encompasses the modulation of structural and functional processes of axons, dendrites, and synapses. The range of structural elements that comprise plasticity includes long-term potentiation (a cellular correlate of learning and memory), synaptic efficacy and remodelling, synaptogenesis, axonal sprouting and dendritic remodelling, and neurogenesis and recruitment...
January 13, 2017: CNS & Neurological Disorders Drug Targets
https://www.readbyqxmd.com/read/28071890/peptide-conjugates-of-benzene-carboxylic-acids-as-agonists-and-antagonists-of-amylin-aggregation
#7
Ruel Z B Desamero, Adam A Profit, Jayson Del Rosario Vedad
Human islet amyloid polypeptide (hIAPP), also known as amylin, is a 37 residue peptide hormone that is stored and co-secreted with insulin. hIAPP plays a pivotal role in type 2 diabetes and is the major component of amyloid deposits found in the pancreas of patients afflicted with the disease. The self-assembly of hIAPP and the formation of amyloid is linked to the death of insulin producing -cells. Recent findings suggest soluble hIAPP oligomers are the cytotoxic species responsible for -cell loss whereas amyloid fibrils themselves may indeed be innocuous...
January 10, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28071842/tip-enhanced-raman-spectroscopy-to-distinguish-toxic-oligomers-from-a%C3%AE-1-42-fibrils-at-the-nanometer-scale
#8
Sébastien Bonhommeau, David Talaga, Julien Hunel, Christophe Cullin, Sophie Lecomte
For the first time, natural Aβ1-42 fibrils (WT) implicated in Alzheimer's disease, as well as two synthetic mutants forming less toxic amyloid fibrils (L34T) and highly toxic oligomers (oG37C), are chemically characterized at the scale of a single structure using tip-enhanced Raman spectroscopy (TERS). While the proportion of TERS features associated with amino acid residues is similar for the three peptides, a careful examination of amide I and amide III bands allows us to clearly distinguish WT and L34T fibers organized in parallel β-sheets from the small and more toxic oG37C oligomers organized in anti-parallel β-sheets...
January 10, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28069414/peptides-derived-from-%C3%AE-lactalbumin-membrane-binding-helices-oligomerize-in-presence-of-lipids-and-disrupt-bilayers
#9
Øyvind Strømland, Ørjan S Handegård, Morten G Larsen, Hanzhen Wen, Øyvind Halskau
Helix A and -C of α-Lactalbumin, a loosely folded amphitropic protein, perturb lipid monolayers by the formation of amyloid pore-like structures. To investigate whether these helices are able to disrupt fully formed bilayers, we designed peptides comprised of Helix A and -C, and investigated their membrane-perturbing properties. The peptides, designated A-Cage-C and A-Lnk-C, were prepared with tryptophan sites in the helical and the spacer segments in order to monitor which part were involved in membrane association under given conditions...
January 6, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28067349/the-synergistic-effect-between-klvff-and-self-assembly-chaperones-on-both-disaggregation-of-beta-amyloid-fibrils-and-reducing-consequent-toxicity
#10
Aoting Qu, Fan Huang, Ang Li, Huiru Yang, Hao Zhou, Jiafu Long, Linqi Shi
By combining KLVFF peptide and self-assembly chaperone we fabricate a new system to achieve the synchronization between Aβ fibril disaggregation and reducing toxicity of Aβ fragments (monomers or oligomers) that consequently formed. When the KLVFF peptides disaggregate fibrils into fragments, the hydrophobic domains of self-assembly chaperones promptly bind them at the same time. This binding blocks the re-aggregation of the fragments and their interaction with cells, and hence reduces the toxicity of these dangerous fragments...
January 19, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28061384/oligomeric-amyloid-%C3%AE-peptide-disrupts-olfactory-information-output-by-impairment-of-local-inhibitory-circuits-in-rat-olfactory-bulb
#11
Bin Hu, Chi Geng, Xiao-Yu Hou
Although early olfactory dysfunction has been found in patients with Alzheimer's disease, the underlying mechanisms remain unclear. In this study, we investigated whether and how oligomeric amyloid-β peptide (Aβ) affects the responses of mitral cells (MCs). We found that oligomeric Aβ1-42 increased spontaneous and evoked firing rates but decreased the ratio of evoked to spontaneous firings in MCs. Aβ1-42 oligomers showed no impact on the hyperactivity exerted by pharmacological blockage of GABAA receptors, suggesting an involvement of GABAergic inhibitory transmission in Aβ1 to 42-induced over-excitability...
December 14, 2016: Neurobiology of Aging
https://www.readbyqxmd.com/read/28061031/inhibition-and-degradation-of-amyloid-beta-a%C3%AE-40-fibrillation-by-designed-small-pep-tide-a-combined-spectroscopy-microscopy-and-cell-toxicity-study
#12
Anirban Ghosh, Nibedita Pradhan, Swapna Bera, Aritreyee Datta, Janarthanan Krishnamoorthy, Nikhil R Jana, Anirban Bhunia
A designed non-toxic, non-hemolytic 11-residue peptide, NF11 (NAVRWSLMRPF) not only inhibits the aggregation of Amyloid beta (Aβ40) protein but also disaggregates the pre-formed oligomers and mature Aβ fibrils thereby reducing associated-toxicity. NMR experiments provide evidence of NF11's ability to inhibit fibril formation, primarily through interaction with the N-terminus region as well as the central hydrophobic cluster of Aβ40. NF11 has micro molar binding affinity towards both monomeric and aggregated species for efficient clearance of toxic aggregates...
January 6, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28060833/wnt-signaling-prevents-the-a%C3%AE-oligomer-induced-mitochondrial-permeability-transition-pore-opening-preserving-mitochondrial-structure-in-hippocampal-neurons
#13
Macarena S Arrázola, Eva Ramos-Fernández, Pedro Cisternas, Daniela Ordenes, Nibaldo C Inestrosa
Alzheimer's disease (AD) is a neurodegenerative disorder mainly known for synaptic impairment and neuronal cell loss, affecting memory processes. Beside these damages, mitochondria have been implicated in the pathogenesis of AD through the induction of the mitochondrial permeability transition pore (mPTP). The mPTP is a non-selective pore that is formed under apoptotic conditions, disturbing mitochondrial structure and thus, neuronal viability. In AD, Aβ oligomers (Aβos) favor the opening of the pore, activating mitochondria-dependent neuronal cell death cascades...
2017: PloS One
https://www.readbyqxmd.com/read/28053038/large-soluble-oligomers-of-amyloid-%C3%AE-protein-from-alzheimer-brain-are-far-less-neuroactive-than-the-smaller-oligomers-to-which-they-dissociate
#14
Ting Yang, Shaomin Li, Huixin Xu, Dominic M Walsh, Dennis J Selkoe
: Soluble oligomers of amyloid β-protein (oAβ) isolated from the brains of Alzheimer's disease (AD) patients have been shown experimentally (in the absence of amyloid plaques) to impair hippocampal synaptic plasticity, decrease synapses, induce tau hyperphosphorylation and neuritic dystrophy, activate microglial inflammation, and impair memory in normal adult rodents. Nevertheless, there has been controversy about what types of oligomers actually confer these AD-like phenotypes. Here, we show that the vast majority of soluble Aβ species obtained from brains of humans who died with confirmed AD elute at high molecular weight (HMW) on nondenaturing size-exclusion chromatography...
January 4, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28043778/neuritogenic-activity-of-bi-functional-bis-tryptoline-triazole
#15
Jutamas Jiaranaikulwanitch, Sarin Tadtong, Piyarat Govitrapong, Valery V Fokin, Opa Vajragupta
Alzheimer's disease (AD) is a common neurodegenerative disorder, one of the hallmarks of which is the deposition of aggregated β-amyloid peptides (Aβ40,42) as plaques in the brain. Oligomers of these peptides have been reported to be toxic and to inhibit neurite outgrowth, as evidenced by neurite dystrophy and significant loss of synaptic connectivity of neurons in the AD brain resulting in cognitive decline. These peptides also react with biological metal in the brain to generate free radicals, thereby aggravating neuronal cell injury and death...
December 23, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28034781/increased-susceptibility-to-a%C3%AE-toxicity-in-neuronal-cultures-derived-from-familial-alzheimer-s-disease-psen1-a246e-induced-pluripotent-stem-cells
#16
Enrique Armijo, Cesar Gonzalez, Mohammad Shahnawaz, Andrea Flores, Brian Davis, Claudio Soto
Alzheimer's disease (AD) is the most common cause of late-life dementia and represents one of the leading causes of death worldwide. The generation of induced pluripotent stem cells (iPSC) has facilitated the production and differentiation of stem cells from patients somatic cells, offering new opportunities to model AD and other diseases in vitro. In this study, we generated iPSCs from skin fibroblasts obtained from a healthy individual, as well as sporadic (sAD) and familial AD (fAD, PSEN1-A246E mutation) patients...
December 26, 2016: Neuroscience Letters
https://www.readbyqxmd.com/read/28031465/aggregation-of-full-length-immunoglobulin-light-chains-from-al-amyloidosis-patients-is-remodeled-by-epigallocatechin-3-gallate
#17
Kathrin Andrich, Ute Hegenbart, Christoph Kimmich, Niraja Kedia, H Robert Bergen, Stefan Schönland, Erich E Wanker, Jan Bieschke
Intervention into amyloid deposition with anti-amyloid agents like the polyphenol Epigallocatechin-3-gallate (EGCG) is emerging as an experimental secondary treatment strategy in systemic light chain amyloidosis (AL). In both AL and Multiple Myeloma (MM), soluble immunoglobulin light chains (LC) are produced by clonal plasma cells, but only in AL they form amyloid deposits in vivo. We investigated the amyloid formation of patient-derived LC and their susceptibility to EGCG in vitro to probe commonalities and systematic differences in their assembly mechanisms...
December 28, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28026168/synthetic-models-of-quasi-stable-amyloid-%C3%AE-40-oligomers-with-significant-neurotoxicity
#18
Yumi Irie, Kazuma Murakami, Mizuho Hanaki, Yusuke Hanaki, Takashi Suzuki, Yoko Monobe, Tomoyo Takai, Ken-Ichi Akagi, Taiji Kawase, Kenji Hirose, Kazuhiro Irie
The formation of soluble oligomers of amyloid β42 and 40 (Aβ42, Aβ40) is the initial event in the pathogenesis of Alzheimer's disease (AD). Based on previous systematic proline replacement and solid-state NMR, we proposed a toxic dimer structure of Aβ42, a highly aggregative alloform, with a turn at positions 22 and 23, and a hydrophobic core in the C-terminal region. However, in addition to Aβ42, Aβ40 dimers can also contribute to AD progression because of the more abundance of Aβ40 monomer in biological fluids...
January 12, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28011193/monitoring-ca-2-elevations-in-individual-astrocytes-upon-local-release-of-amyloid-beta-in-acute-brain-slices
#19
Olga Tyurikova, Kaiyu Zheng, Annika Rings, Anna Drews, David Klenerman, Dmitri A Rusakov
The pathogenesis of Alzheimer's disease (AD) is thought to involve acute neurotoxic effects exerted by oligomeric forms of amyloid-β 1-42 (Aβ). Application of Aβ oligomers in physiological concentrations have been shown to transiently elevate internal Ca(2+) in cultured astroglia. While the cellular machinery involved has been extensively explored, to what degree this important signalling cascade occurs in organised brain tissue has remained unclear. Here we adapted two-photon excitation microscopy and calibrated time-resolved imaging (FLIM), coupled with patch-clamp electrophysiology, to monitor Ca(2+) concentration ([Ca(2+)]) inside individual astrocytes and principal neurons in acute brain slices...
December 20, 2016: Brain Research Bulletin
https://www.readbyqxmd.com/read/28009077/inflammasomes-as-therapeutic-targets-for-alzheimer-s-disease
#20
Claire S White, Catherine B Lawrence, David Brough, Jack Rivers-Auty
Alzheimer's disease is the most common form of progressive dementia, typified initially by short term memory deficits which develop into a dramatic global cognitive decline. The classical hall marks of Alzheimer's disease include the accumulation of amyloid oligomers and fibrils, and the intracellular formation of neurofibrillary tangles of hyperphosphorylated tau. It is now clear that inflammation also plays a central role in the pathogenesis of the disease through a number of neurotoxic mechanisms. Microglia are the key immune regulators of the CNS which detect amyloidopathy through cell surface and cytosolic pattern recognition receptors (PRRs) and respond by initiating inflammation through the secretion of cytokines such as interleukin-1β (IL-1β)...
December 23, 2016: Brain Pathology
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