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Amyloid oligomers

Silvia A Purro, Andrew J Nicoll, John Collinge
The initial report that cellular prion protein (PrPC) mediates toxicity of amyloid-β species linked to Alzheimer's disease was initially treated with scepticism, but growing evidence supports this claim. That there is a high-affinity interaction is now clear, and its molecular basis is being unraveled, while recent studies have identified possible downstream toxic mechanisms. Determination of the clinical significance of such interactions between PrPC and disease-associated amyloid-β species will require experimental medicine studies in humans...
February 15, 2018: Biological Psychiatry
Raluca Ștefănescu, Loredana Lupu, Marilena Manea, Roxana E Iacob, Michael Przybylski
Alzheimer disease is a neurodegenerative disease affecting an increasing number of patients worldwide. Current therapeutic strategies are directed to molecules capable to block the aggregation of the β-amyloid(1-42) (Aβ) peptide and its shorter naturally occurring peptide fragments into toxic oligomers and amyloid fibrils. Aβ-specific antibodies have been recently developed as powerful antiaggregation tools. The identification and functional characterization of the epitope structures of Aβ antibodies contributes to the elucidation of their mechanism of action in the human organism...
January 2018: Journal of Peptide Science: An Official Publication of the European Peptide Society
Mimi Nick, Yibing Wu, Nathan W Schmidt, Stanley B Prusiner, Jan Stöhr, William F DeGrado
The hydrophobic Aβ peptide is highly aggregation prone; it first forms soluble oligomers, which then convert into the amyloid fibrils found in the cerebral plaques of Alzheimer's disease. It is generally understood that as the peptide concentration of Aβ increases, the fibrillization process is accelerated, but we examine the limits on this phenomenon. We found that once a threshold concentration of Aβ is exceeded, a stable oligomer is formed at the expense of fibril formation. The suppression of fibril formation was observed by amyloid-binding dye Thioflavin T and solution nuclear magnetic resonance (NMR)...
January 10, 2018: Biopolymers
Meghomukta Mukherjee, Jagannath Jana, Subhrangsu Chatterjee
Protein misfolding is interrelated to several diseases, including neurodegenerative diseases and type II diabetes. Misfolded/unfolded proteins produce soluble oligomers that accumulate into "amyloid plaques". Inhibition of amyloid-plaque formation by those misfolded/unfolded proteins will lead to the invention of new therapeutic approaches for amyloid-related diseases. Herein, methylene blue (MB), a well-defined drug against multiple diseases and disorders, is used to impede insulin fibrillation. In this study, we perform an array of in vitro experiments to monitor the effects of MB on the fibrillation of bovine insulin...
January 2018: ChemistryOpen
V Guru KrishnaKumar, Ashim Paul, Ehud Gazit, Daniel Segal
Intra-cellular tau protein tangles and extra-cellular β-amyloid plaques are hallmarks of Alzheimer's disease (AD), characterized by the conversion of natively unfolded monomeric protein/peptide into misfolded β-sheet rich aggregates. Therefore, inhibiting the aggregation cascade or disassembling the pre-formed aggregates becomes a pivotal event in disease treatment. In the present study, we show that Naphthoquinone-Tryptophan hybrids, i.e., NQTrp and Cl-NQTrp significantly disrupted the pre-formed fibrillar aggregates of Tau-derived PHF6 (VQIVYK) peptide and full-length tau protein in vitro, in a dose-dependent manner as evident from ThS assay, CD spectroscopy, and TEM...
January 8, 2018: Scientific Reports
Atsuhiko Taniguchi
 Amyloid proteins and peptides form aggregates which lead to amyloid diseases. For example, Alzheimer's disease-related amyloid β (Aβ) forms oligomers, protofibrils, and amyloid fibrils, which exhibit neurotoxicity. Controlling the aggregation and toxicity of Aβ would be a therapeutic strategy for the treatment of Alzheimer's disease. Recently, we have investigated an artificial oxygenative modification (chemical introduction of oxygen atoms) of amyloid proteins using a photocatalyst, which attenuated the aggregation potency and toxicity of these proteins...
2018: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
Anna Wilkaniec, Magdalena Gąssowska-Dobrowolska, Marcin Strawski, Agata Adamczyk, Grzegorz A Czapski
BACKGROUND: Cyclin-dependent kinase 5 (Cdk5) belongs to the family of proline-directed serine/threonine kinases and plays a critical role in neuronal differentiation, migration, synaptogenesis, plasticity, neurotransmission and apoptosis. The deregulation of Cdk5 activity was observed in post mortem analysis of brain tissue of Alzheimer's disease (AD) patients, suggesting the involvement of Cdk5 in the pathomechanism of this neurodegenerative disease. However, our recent study demonstrated the important function of Cdk5 in regulating inflammatory reaction...
January 4, 2018: Journal of Neuroinflammation
Franziska Kundel, Suman De, Patrick Flagmeier, Mathew H Horrocks, Magnus Kjaergaard, Sarah L Shammas, Sophie E Jackson, Christopher M Dobson, David Klenerman
As a key player of the protein quality control network of the cell, the molecular chaperone Hsp70 inhibits the aggregation of the amyloid protein tau. To date, the mechanism of this inhibition and the tau species targeted by Hsp70 remain unknown. This is partly due to the inherent difficulty of studying amyloid aggregates because of their heterogeneous and transient nature. Here, we used ensemble and single-molecule fluorescence measurements to dissect how Hsp70 counteracts the self-assembly process of K18 tau with the pathological deletion ∆K280...
January 4, 2018: ACS Chemical Biology
Chunyan Deng, Hui Liu, Manman Zhang, Honghua Deng, Chunyang Lei, Lu Shen, Bin Jiao, Qiuyun Tu, Yan Jin, Lei Xiang, Wei Deng, Yongfan Xie, Juan Xiang
Herein, a light-up non-thiolated aptasensor was developed for low-mass soluble amyloid-β40 oligomers (LS-Aβ40-O). Au nanoparticle (AuNP) was employed as a colorimetric probe, and the non-thiolated aptamer (Apt) was adsorbed on AuNP surfaces, acting as a binding element for LS-Aβ40-O. The aggregation of AuNPs was induced when Apt-modified AuNPs (Apt@AuNPs) were under high salt conditions. However, upon addition of LS-Aβ40-O into the Apt@AuNP solution, the salt-tolerance of AuNPs was greatly enhanced. Further studies confirmed that the formed LS-Aβ40-O/Apt complex was attached onto AuNP surfaces via the interaction between LS-Aβ40-O and Au, which led to the electrostatic and steric stabilization of AuNPs under high salt conditions...
January 4, 2018: Analytical Chemistry
Ning Xiang, Yuan Lyu, Xiao Zhu, Ganesan Narsimhan
Some amyloid related proteins/peptides are involved in aggregation and pore formation in phospholipid membranes (cell membranes), which result in a variety of neurological disorders such as Alzheimer's disease, Parkinson's disease and Huntington disease. In this research, the mechanism of pore formation by β amyloid (Aβ) peptides was investigated using molecular dynamics simulation by simulating the interaction of the Aβ(11-42) peptide, with a lipid membrane and the potential of the mean force of interaction was evaluated...
January 4, 2018: Physical Chemistry Chemical Physics: PCCP
Narendra Nath Jha, Srivastav Ranganathan, Rakesh Kumar, Surabhi Mehra, Rajlaxmi Panigrahi, Ambuja Navalkar, Dhiman Ghosh, Ashutosh Kumar, Ranjith Padinhateeri, Samir K Maji
Aggregation of α-synuclein (α-Syn) into neurotoxic oligomers and amyloid fibrils is suggested to be the pathogenic mechanism for Parkinson's disease (PD). Recent studies have indicated that oligomeric species of α-Syn are more cytotoxic as compared to their mature fibrillar counterparts, which are responsible for dopaminergic neuronal cell death in PD. Therefore, the effective therapeutic strategies to tackle aggregation-associated diseases would be to either prevent aggregation or modulate the aggregation process to minimize the formation of toxic oligomers during aggregation...
December 29, 2017: Biochemistry
Mariana A de Godoy, Leonardo M Saraiva, Luiza R P Carvalho, Andreia Vasconcelos-Dos-Santos, Hellen J V Beiral, Alane Bernardo Ramos, Livian R de Paula Silva, Renata B Leal, Victor H S Monteiro, Carolina V Braga, Carlla A de Araujo-Silva, Leandro C Sinis, Victor Bodart Santos, Tais Hanae Kasai Brunswick, Carolina de Lima Alcantara, Ana Paula C A Lima, Narcisa L da Cunha E Silva, Antonio Galina, Adalberto Vieyra, Fernanda G De Felice, Rosalia Mendez-Otero, Sergio T Ferreira
Alzheimer disease (AD) is a disabling and highly prevalent neurodegenerative condition, for which there are no effective therapies. Soluble oligomers of the amyloid-beta peptide (AβOs) are thought to be proximal neurotoxins involved in early neuronal oxidative stress and synapse damage, ultimately leading to neurodegeneration and memory impairment in AD. The aim of the current study was to evaluate the neuroprotective potential of mesenchymal stem cells (MSCs) against the deleterious impact of AβOs on hippocampal neurons...
December 28, 2017: Journal of Biological Chemistry
Sara Sanz-Blasco, Maria Calvo-Rodríguez, Erica Caballero, Monica Garcia-Durillo, Lucía Nunez, Carlos Villalobos
Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Unfortunately, recent trials have failed in providing compelling evidence of neuroprotection. Discussion as to why NSAIDs effectivity is uncertain is ongoing. Possible explanations include the view that NSAIDs and other possible disease-modifying drugs should be provided before the patients develop symptoms of AD or cognitive decline. In addition, NSAID targets for neuroprotection are unclear...
December 27, 2017: Current Alzheimer Research
Xuehan Jiang, Yang Cao, Wei Han
The recent finding that the surface of amyloid-β (Aβ) fibril can recruit Aβ peptides and convert them into toxic oligomers has rendered fibril surfaces attractive as inhibition targets. Through extensive simulations with hybrid-resolution and all-atom models, we have investigated how Aβ1-40 recognizes its own fibril surfaces. These calculations give a ~2.6-5.6μM half-saturation concentration of Aβ on the surface (cf. experimental value ~6μM). Aβ was found to preferentially bind to region 16-24 of Aβ40 fibrils through both electrostatic and van der Waals forces...
December 27, 2017: ACS Chemical Neuroscience
Esmail A Elbassal, Clifford Morris, Thomas W Kent, Richard Lantz, Bimlesh Ojha, Ewa P Wojcikiewicz, Deguo Du
The process of amyloid-β (Aβ) amyloid formation is pathologically linked to Alzheimer's disease (AD). The identification of Aβ amyloids and intermediates that are crucial players in the pathology of AD is critical for exploring the underlying mechanism of Aβ aggregation and the diagnosis of the disease. Herein, we performed a gold nanoparticle (AuNP)-based study to detect the formation of Aβ amyloid fibrils and oligomers. Our results demonstrate that the intensity of the surface plasmon resonance (SPR) absorption band of the AuNPs is sensitive to the quantity of Aβ40 amyloids...
September 14, 2017: Journal of Physical Chemistry. C, Nanomaterials and Interfaces
Jerson L Silva, Elio A Cino, Iaci N Soares, Vitor F Ferreira, Guilherme A P de Oliveira
Prion-like behavior of several amyloidogenic proteins has been demonstrated in recent years. Despite having functional roles in some cases, irregular aggregation can have devastating consequences. The most commonly known amyloid diseases are Alzheimer's, Parkinson's, and Transmissible Spongiform Encephalopathies (TSEs). The pathophysiology of prion-like diseases involves the structural transformation of wild-type (wt) proteins to transmissible forms that can convert healthy proteins, generating aggregates. The mutant form of tumor suppressor protein, p53, has recently been shown to exhibit prion-like properties...
December 20, 2017: Accounts of Chemical Research
Xu Han, Gefei He
The last decades have witnessed a growing global burden of Alzheimer's disease (AD). Evidence indicates the onset and progression of AD is associated with β-amyloid (Aβ) peptide fibrillation. As such, there is a strong passion with discovering potent Aβ fibrillation inhibitors that can be developed into antiamyloiddogenic agents for AD treatment. Current challenges arisen with this development involve with Aβ oligomer toxicity suppression and Blood Brain Barrier penetration capability. Considering most natural or biological events, one would observe that there is usually a "seed" to direct natural materials to assembly in response to a certain stimulation...
December 18, 2017: ACS Chemical Neuroscience
Michelle Hupert, Anne Elfgen, Elena Schartmann, Sarah Schemmert, Brigitte Buscher, Janine Kutzsche, Dieter Willbold, Beatrix Santiago-Schübel
During preclinical drug development, a method for quantification of unlabeled compounds in blood plasma samples from treatment or pharmacokinetic studies in mice is required. In the current work, a rapid, specific, sensitive and validated liquid chromatography mass-spectrometric UHPLC-ESI-QTOF-MS method was developed for the quantification of the therapeutic compound RD2 in mouse plasma. RD2 is an all-D-enantiomeric peptide developed for the treatment of Alzheimer's disease, a progressive neurodegenerative disease finally leading to dementia...
December 8, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Dario Carradori, Claudia Balducci, Francesca Re, Davide Brambilla, Benjamin Le Droumaguet, Orfeu Flores, Alice Gaudin, Simona Mura, Gianluigi Forloni, Lara Ordoñez-Gutierrez, Francisco Wandosell, Massimo Masserini, Patrick Couvreur, Julien Nicolas, Karine Andrieux
Alzheimer's disease (AD) is a neurodegenerative disorder related, in part, to the accumulation of amyloid-β peptide (Aβ) and especially the Aβ peptide 1-42 (Aβ1-42). The aim of this study was to design nanocarriers able to: (i) interact with the Aβ1-42 in the blood and promote its elimination through the "sink effect" and (ii) correct the memory defect observed in AD-like transgenic mice. To do so, biodegradable, PEGylated nanoparticles were surface-functionalized with an antibody directed against Aβ1-42...
December 14, 2017: Nanomedicine: Nanotechnology, Biology, and Medicine
Angie C A Chiang, Stephanie W Fowler, Rohit Reddy, Olga Pletnikova, Juan C Troncoso, Mathew A Sherman, Sylvain E Lesne, Joanna L Jankowsky
Despite increasing appreciation that oligomeric amyeloid beta (Aβ) may contribute to cognitive decline of Alzheimer disease, defining the most critical forms has been thwarted by the changeable nature of these aggregates and the varying methods used for detection. Here, using a broad approach, we quantified Aβ oligomers during the evolution of cognitive deficits in an aggressive model of Aβ amyloidosis. Amyloid precursor protein/tetracycline transactivator mice underwent behavioral testing at 3, 6, 9, and 12 months of age to evaluate spatial learning and memory, followed by histological assessment of amyloid burden and biochemical characterization of oligomeric Aβ species...
December 14, 2017: American Journal of Pathology
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