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Amyloid oligomers

Jing-Ming Shi, Jie Pei, En-Qi Liu, Lin Zhang
The structure and state of amyloid-β peptide (Aβ) oligomers often need to be checked by reliable experimental methods. Electrophoresis is a commonly applied measurement method. However, due to the presence of detergents, oligomers are easily broken during electrophoresis, which makes it very hard to accurately assess Aβ aggregate states. In the current study, bis(sulfosuccinimidyl) suberate (BS3) was used to cross-link Aβ1-42 oligomers prior to electrophoresis. When compared to a previously reported Aβ cross-linking agent, glutaraldehyde, it was quite apparent that BS3 is more suitable for detecting intra-membrane Aβ oligomers and extra-membrane Aβ oligomers states...
2017: PloS One
Prasad Tammineni, Qian Cai
Macroautophagy/autophagy plays a key role in cellular quality control by eliminating protein aggregates and damaged organelles, which is essential for the maintenance of neuronal homeostasis. Defective autophagy has been implicated in the pathogenesis of Alzheimer disease (AD). In AD brains, autophagic vacuoles (AVs) accumulate massively within dystrophic neurites. This raises a fundamental question as to whether impaired autophagic clearance contributes to AD-associated autophagic stress. We recently revealed that AD neurons display defective retrograde transport and accumulation of amphisomes predominantly in axons and presynaptic terminals...
February 28, 2017: Autophagy
Gesi Wen, Wenjing Qin, Daoyuan Chen, Youqiao Wang, Xin Yue, Ziyi Liu, Yingnan Cao, Jun Du, Binhua Zhou, Xianzhang Bu
Amyloid-β (Aβ) oligomers are causative agents triggering AD pathogenesis, but their elimination remains challenging. We herein reported a natural cyclopeptide tyrocidine A prevents and reverses amyloidogenesis without Aβ oligomer accumulation by stabilizing the monomeric, but not the oligomeric state of Aβ peptides.
March 20, 2017: Chemical Communications: Chem Comm
Gisele S Seixas da Silva, Helen M Melo, Mychael V Lourenco, Natalia de M Lyra E Silva, Marcelo B de Carvalho, Soniza Alves-Leon, Jorge M de Souza, William L Klein, Wagner S da-Silva, Sergio T Ferreira, Fernanda G De Felice
AMP-activated kinase (AMPK) is a key player in energy sensing and metabolic reprogramming under cellular energy restriction. Several studies have linked impaired AMPK function to peripheral metabolic diseases such as diabetes. However, the impact of neurological disorders, such as Alzheimer disease (AD), on AMPK function and downstream effects of altered AMPK activity on neuronal metabolism have been investigated only recently. Here, we report the impact of A β oligomers (AβOs), synaptotoxins that accumulate in AD brains, on neuronal AMPK activity...
March 16, 2017: Journal of Biological Chemistry
Syed H Omar, Christopher J Scott, Adam S Hamlin, Hassan K Obied
Self-assembly of amyloid beta peptide (Aβ) into the neurotoxic oligomers followed by fibrillar aggregates is a defining characteristic of Alzheimer's disease (AD). Several lines of proposed hypotheses have suggested the mechanism of AD pathology, though the exact pathophysiological mechanism is not yet elucidated. The poor understanding of AD and multitude of adverse responses reported from the current synthetic drugs are the leading cause of failure in the drug development to treat or halt the progression of AD and mandate the search for safer and more efficient alternatives...
March 3, 2017: Journal of Nutritional Biochemistry
Marina Ramirez-Alvarado, David R Barnidge, David L Murray, Angela Dispenzieri, Marta Marin-Argany, Christopher J Dick, Shawna A Cooper, Samih H Nasr, Christopher J Ward, Surendra Dasari, Víctor H Jiménez-Zepeda, Nelson Leung
Immunoglobulin light chain (AL) amyloidosis is a fatal complication of B-cell proliferation secondary to deposition of amyloid fibrils in various organs. Urinary exosomes (UEX) are the smallest of the microvesicles excreted in the urine. Previously, we found UEX of patients with AL amyloidosis contained immunoglobulin light chain (LC) oligomers that patients with multiple myeloma did not have. To further explore the role of the LC oligomers, UEX was isolated from an AL amyloidosis patient with progressive renal disease despite achieving a complete response...
March 10, 2017: American Journal of Hematology
Greg Goldblatt, Lucia Cilenti, Jason O Matos, Briana Lee, Nicholas Ciaffone, Qing X Wang, Laurene Tetard, Ken Teter, Suren A Tatulian
Amyloid β (Aβ) peptide plays a major role in Alzheimer's disease (AD) and occurs in multiple forms, including pyroglutamylated Aβ (AβpE). Identification and characterization of the most cytotoxic Aβ species is necessary for advancement in AD diagnostics and therapeutics. While in brain tissue multiple Aβ species act in combination, structure/toxicity studies and immunotherapy trials have been focused on individual forms of Aβ. As a result, the molecular composition and the structural features of "toxic Aβ oligomers" have remained unresolved...
March 13, 2017: FEBS Journal
Yang Song, Edwin G Moore, Yanshu Guo, Jeffrey S Moore
Amyloid aggregation and deposition are associated with many intractable human diseases. Although the inhibition of amyloid protein aggregation has been well-studied, the disaggregation and dissolution of existing amyloid fibrils is less known. Taking a fibrillar assembly of amyloid β (Aβ) peptide as the model system, here we report multivalent polymer-peptide conjugates (mPPCs) that disassemble preformed Aβ fibrils into dispersible sub-100 nm structures. Atomic force microscopy and dynamic light scattering studies show that the disassembly rate of preformed Aβ fibrils is controlled by the molecular weight of mPPCs...
March 14, 2017: Journal of the American Chemical Society
Evgenia G Matveeva, Jonathan R Moll, Mariam M Khan, Richard B Thompson, Richard O Cliff
Immunoassays such as enzyme-linked immunosorbent assays (ELISAs) are widely used for diagnostics; however, antibodies as detection reagents may be insufficiently selective and have other shortcomings. We present a novel non-antibody-based detection method based on binding target molecules to peptides (used as recognition molecules): a surface assay for A-β oligomers employing a peptide comprising amino acid residues of the human β-amyloid protein (Pronucleon peptide) as the capture agent. For the sake of convenience, we term this the "Pronucleon peptide-linked immunosorbent assay", or PLISA...
March 21, 2017: ACS Chemical Neuroscience
Alireza Abdolvahabi, Yunhua Shi, Sanaz Rasouli, Corbin M Croom, Amir Aliyan, Angel A Marti, Bryan F Shaw
Over 150 mutations in SOD1 (superoxide dismutase-1) cause amyotrophic lateral sclerosis (ALS), presumably by accelerating SOD1 amyloidogenesis. Like many nucleation processes, SOD1 fibrillization is stochastic (in vitro), which inhibits determination of aggregation rates (and obscures whether rates correlate with patient phenotypes). Here, we diverged from classical chemical kinetics and used Kaplan-Meier estimators to quantify the probability of apo-SOD1 fibrillization (in vitro) from ~ 10(3) replicate amyloid assays of wild-type (WT) SOD1 and nine ALS variants...
March 14, 2017: ACS Chemical Neuroscience
Jordano Brito-Moreira, Mychael V Lourenco, Mauricio M Oliveira, Juliana F S Vital, Felipe C Ribeiro, José Henrique Ledo, Luan P Diniz, Margaret H Magdesian, Helen M Melo, Fernanda Barros-Aragão, Jorge M de Souza, Soniza V Alves-Leon, Flavia C A Gomes, Julia R Clarke, Cláudia P Figueiredo, Fernanda G De Felice, Sergio T Ferreira
Brain accumulation of the amyloid-β protein (Aβ) and synapse loss are neuropathological hallmarks of Alzheimer disease (AD). Aβ oligomers (AβOs) are synaptotoxins that build up in the brains of patients and are thought to contribute to memory impairment in AD. Thus, identification of novel synaptic components that are targeted by AβOs will likely contribute to the elucidation of disease-relevant mechanisms. Trans-synaptic interactions between neurexins (Nrxs) and neuroligins (NLs) are essential for synapse structure, stability and function, and reduced NL levels have been recently associated with AD...
March 10, 2017: Journal of Biological Chemistry
Saima Nusrat, Nida Zaidi, Mohammad Khursheed Siddiqi, Masihuz Zaman, Ibrar Ahmed Siddique, Mohammad Rehan Ajmal, Ali Saber Abdelhameed, Rizwan Hasan Khan
In spite of the fact that amyloid related neurodegenerative illnesses and non-neuropathic systemic amyloidosis have allured the research endeavors, as no cure has been announced yet apart from symptomatic treatment. Therapeutic agents which can reduce or disaggregate those toxic oligomers and fibrillar species have been studied with more compounds are on their way. The current research work describes comprehensive biophysical, computational and microscopic studies which reveal that L-3, 4-dihydroxyphenylalanine (L-Dopa) have indisputable efficacy to hinder the heat induced amyloid fibrillation of the human lysozyme (HL) and also preserve the fibril disaggregating potential...
March 7, 2017: International Journal of Biological Macromolecules
Margherita Romeo, Matteo Stravalaci, Marten Beeg, Alessandro Rossi, Fabio Fiordaliso, Alessandro Corbelli, Mario Salmona, Marco Gobbi, Alfredo Cagnotto, Luisa Diomede
The 24-residue peptide humanin (HN) has been proposed as peptide-based inhibitors able to interact directly with amyloid-β (Aβ) oligomers and interfere with the formation and/or biological properties of toxic Aβ species. When administered exogenously HN, or its synthetic S14G-derivative (HNG), exerted multiple cytoprotective effects, counteracting the Aβ-induced toxicity. Whether these peptides interact directly with Aβ, particularly with the soluble oligomeric assemblies, remains largely unknown. We here investigated the ability of HN and HNG to interact directly with highly aggregating Aβ42, and interfere with the formation and toxicity of its oligomers...
March 6, 2017: Journal of Alzheimer's Disease: JAD
Mary Dutta, Venkata Satish Kumar Mattaparthi
Recent experimental data revealed that small, soluble Amyloid beta (Aβ42) oligomers, especially dimers impair synaptic plasticity and memory leading to Alzheimer's disease. Here, we have studied dimerization of Aβ42/Aβ42 homo-dimer and Aβ40/Aβ42 hetero-dimer in terms of free energy profile by all-atom simulations using the ff99SB force field. We have found that in the presence of Aβ40 peptide, there exists a strong tendency to form a hetero-dimer with Aβ42 peptide, suggesting that a possible co-oligomerization...
March 13, 2017: Journal of Biomolecular Structure & Dynamics
Guanbin Gao, Mingxi Zhang, Dejun Gong, Rui Chen, Xuejiao Hu, Taolei Sun
A significant pathological signature of Alzheimer's disease (AD) is the deposition of amyloid-β (Aβ) plaques in the brain and the synaptic dysfunction and neurodegeneration associated with it. Compounds or drugs that inhibit Aβ fibrillation are thus desirable to develop novel therapeutic strategies against AD. Conventional strategies usually require an elaborate design of their molecular structures. Here we report the size-effect of gold nanoparticles (AuNPs) and nanoclusters (AuNCs) in the inhibition of protein amyloidosis...
March 9, 2017: Nanoscale
Sunil Kumar, Andrew D Hamilton
A key molecular species in Alzheimer's disease (AD) is the Aβ42 alloform of Aβ peptide, which is dominant in the amyloid plaques deposited in the brains of AD patients. Recent studies have decisively demonstrated that the prefibrillar soluble oligomers are the neurotoxic culprits and are associated with the pathology of AD. Nascent Aβ42 is predominantly disordered but samples α-helical conformations covering residues 15-24 and 29-35 in the presence of micelles and structure-inducing solvents. In this report, a focused library of oligopyridylamide based α-helical mimetics was designed to target the central α-helix subdomain of Aβ (Aβ13-26)...
March 8, 2017: Journal of the American Chemical Society
Claude Bobo, Stéphane Chaignepain, Sarah Henry, Hélène Vignaud, Alfred Améadan, Christelle Marchal, Enora Prado, James Doutch, Jean-Marie Schmitter, Corinne Nardin, Sophie Lecomte, Christophe Cullin
BACKGROUND: Alzheimer's disease is the most common neurodegenerative disease associated with aggregation of Aβ peptides. Aβ toxicity is mostly related to the capacity of intermediate oligomers to disrupt membrane integrity. We previously expressed Aβ1-42 in a eukaryotic cellular system and selected synthetic variants on their sole toxicity. The most toxic mutant G37C forms stable oligomers. METHODS: Different biophysical methods (Fluorescence spectroscopy, cross-linking, mass spectrometry (MS), Small Angle X-ray Scattering (SAXS), Atomic Force Microscopy (AFM), Transmission Electron Microscopy (TEM), calcein leakage) were used...
March 3, 2017: Biochimica et Biophysica Acta
Yi-Chih Lin, Milton H Repollet-Pedrosa, John J Ferrie, E James Petersson, Zahra Fakhraai
Accurate imaging of nanometer-sized structures and morphologies is essential to characterizing amyloid species formed at various stages of amyloid aggregation. In this article, we examine the effect of different drying procedures on the final morphology of surface-mediated fibrils formed during the incubation period, which may then be mistaken as oligomers or protofibrils intentionally formed in solution for a particular study. Atomic force microscopy results show that some artifacts, such as globules, flakelike structures, and even micrometer-long fibrils, can be produced under various drying conditions...
March 20, 2017: Journal of Physical Chemistry. B
Kichitaro Nakajima, Masatomo So, Kazuma Takahashi, Yoh-Ichi Tagawa, Masahiko Hirao, Yuji Goto, Hirotsugu Ogi
Oligomer species of amyloid β (Aβ) peptides are intensively investigated because of their relevance to Alzheimer's disease (AD), and a stable oligomer will be a cause of AD. In this article, we investigate the structural stability of two representative Aβ1-40 oligomers, which are with and without the β-sheet structure, denoted by β and non-β oligomers, respectively, using optimized ultrasonic irradiation (OUI). Recent studies reveal that OUI significantly accelerates the fibril formation in Aβ1-40 monomers; it is capable of transforming any unstable oligomers into fibrils (the dead-end products) in a short time...
March 16, 2017: Journal of Physical Chemistry. B
Jaya Sharma, Brett T Wisniewski, Emily Paulson, Joanna O Obaoye, Stephen J Merrill, Anita L Manogaran
Prion and other neurodegenerative diseases are associated with misfolded protein assemblies called amyloid. Research has begun to uncover common mechanisms underlying transmission of amyloids, yet how amyloids form in vivo is still unclear. Here, we take advantage of the yeast prion, [PSI (+)], to uncover the early steps of amyloid formation in vivo. [PSI (+)] is the prion form of the Sup35 protein. While [PSI (+)] formation is quite rare, the prion can be greatly induced by overexpression of the prion domain of the Sup35 protein...
December 2017: Scientific Reports
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