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amyloid oligomer

Diti Chatterjee Bhowmick, Sanghamitra Singh, Saurabh Trikha, Aleksandar M Jeremic
Human islet amyloid polypeptide or amylin (hA) is a 37-amino acid peptide hormone produced and co-secreted with insulin by pancreatic β-cells. Under physiological conditions, hA regulates a broad range of biological processes including insulin release and slowing of gastric emptying, thereby maintaining glucose homeostasis. However, under the pathological conditions associated with type 2 diabetes mellitus (T2DM), hA undergoes a conformational transition from soluble random coil monomers to alpha-helical oligomers and insoluble β-sheet amyloid fibrils or amyloid plaques...
October 18, 2017: Handbook of Experimental Pharmacology
Seong Soo A An, Byoung-Sub Lee, Ji Sun Yu, Kuntaek Lim, Gwang Je Kim, Ryan Lee, Shinwon Kim, Sungmin Kang, Young Ho Park, Min Jeong Wang, Young Soon Yang, Young Chul Youn, SangYun Kim
BACKGROUND: A reliable blood-based assay is required to properly diagnose and monitor Alzheimer's disease (AD). Many attempts have been made to develop such a diagnostic tool by measuring amyloid-β oligomers (AβOs) in the blood, but none have been successful in terms of method reliability. We present a multimer detection system (MDS), initially developed for the detection of prion oligomers in the blood, to detect AβOs. METHODS: To characterize Aβ in the blood, plasma was spiked with synthetic amyloid-β (Aβ) and incubated over time...
October 17, 2017: Alzheimer's Research & Therapy
Nabin Kandel, Tianyu Zheng, Qun Huo, Suren A Tatulian
Amyloid β (Aβ) peptide contributes to Alzheimer's disease by a yet unidentified mechanism. In brain tissue, Aβ occurs in various forms, including an undecapeptide Aβ25-35, which exerts neurotoxic effect through mitochondrial dysfunction and/or Ca(2+)-permeable pore formation in cell membranes. This work was aimed at biophysical characterization of membrane binding and pore formation by Aβ25-35. Interaction of Aβ25-35 with anionic and zwitterionic membranes was analyzed by microelectrophoresis. In pore formation experiments, Aβ25-35 was incubated in aqueous buffer to form oligomers and added to Quin-2-loaded vesicles...
October 17, 2017: Journal of Physical Chemistry. B
Yunxiang Sun, Bo Wang, Xinwei Ge, Feng Ding
A direct observation of amyloid aggregation from isolated peptides to cross-β fibrils is crucial for understanding the nucleation-dependence process, but the corresponding macroscopic timescales impose a major computational challenge. Using rapid all-atom discrete molecular dynamics simulations, we capture the oligomerization and fibrillization dynamics of the amyloid core sequences of amyloid-β (Aβ) in Alzheimer's disease and islet amyloid polypeptide (IAPP) in type-2 diabetes, namely Aβ16-22 and IAPP22-28...
October 17, 2017: Physical Chemistry Chemical Physics: PCCP
Patrick C A van der Wel
The aggregation of proteins and peptides into a variety of insoluble, and often non-native, aggregated states plays a central role in many devastating diseases. Analogous processes undermine the efficacy of polypeptide-based biological pharmaceuticals, but are also being leveraged in the design of biologically inspired self-assembling materials. This Trends article surveys the essential contributions made by recent solid-state NMR (ssNMR) studies to our understanding of the structural features of polypeptide aggregates, and how such findings are informing our thinking about the molecular mechanisms of misfolding and aggregation...
October 4, 2017: Solid State Nuclear Magnetic Resonance
Emily H Pilkington, May Lai, Xinwei Ge, William J Stanley, Bo Wang, Miaoyi Wang, Aleksandr Kakinen, Marc-Antoine Sani, Michael R Whittaker, Esteban N Gurzov, Feng Ding, John F Quinn, Thomas P Davis, Pu Chun Ke
Protein aggregation into amyloid fibrils is a ubiquitous phenomenon across the spectrum of neurodegenerative disorders and type 2 diabetes. A common strategy against amyloidogenesis is to minimize the populations of toxic oligomers and protofibrils by inhibiting protein aggregation with small molecules or nanoparticles. However, melanin synthesis in nature is realized by accelerated protein fibrillation to circumvent accumulation of toxic intermediates. Accordingly, we designed and demonstrated the use of star-shaped poly(2-hydroxyethyl acrylate) (PHEA) nanostructures for promoting the aggregation while ameliorating the toxicity of human islet amyloid polypeptide (IAPP), the peptide involved in glycemic control and the pathology of type 2 diabetes...
October 16, 2017: Biomacromolecules
Dixie Bungard, Jacob S Copple, Jing Yan, Jimmy J Chhun, Vlad K Kumirov, Scott G Foy, Joanna Masel, Vicki H Wysocki, Matthew H J Cordes
The de novo evolution of protein-coding genes from noncoding DNA is emerging as a source of molecular innovation in biology. Studies of random sequence libraries, however, suggest that young de novo proteins will not fold into compact, specific structures typical of native globular proteins. Here we show that Bsc4, a functional, natural de novo protein encoded by a gene that evolved recently from noncoding DNA in the yeast S. cerevisiae, folds to a partially specific three-dimensional structure. Bsc4 forms soluble, compact oligomers with high β sheet content and a hydrophobic core, and undergoes cooperative, reversible denaturation...
October 7, 2017: Structure
Christiane Rose, Emilie Dorard, Mickael Audrain, Lucie Gorisse-Hussonnois, Nathalie Cartier, Jérome Braudeau, Bernadette Allinquant
Amyloid precursor protein (APP), a key molecule of Alzheimer disease, is metabolized in 2 antagonist pathways generating the soluble APP alpha (sAPPα) having neuroprotective properties and the beta amyloid (Aβ) peptide at the origin of neurotoxic oligomers, particularly Aβ1-42. Whether extracellular Aβ1-42 oligomers modulate the formation and secretion of sAPPα is not known. We report here that the addition of Aβ1-42 oligomers to primary cortical neurons induced a transient increase in α-secretase activity and secreted sAPPα 6-9 hours later...
September 19, 2017: Neurobiology of Aging
Yiming Wang, David C Latshaw, Carol K Hall
Although some naturally-occurring polyphenols have been found to inhibit amyloid β fibril formation and reduce neuron cell toxicity in vitro, their exact inhibitory mechanism is unknown. In this work, discontinuous molecular dynamics (DMD) combined with the PRIME20 force field and a newly-built inhibitor model are performed to examine the effect of vanillin, resveratrol, curcumin and epigallocatechin-3-gallate (EGCG) on the aggregation of Aβ(17-36) peptides. Four sets of peptide/inhibitor simulations are performed in which inhibitors: (1) bind to Aβ(17-36) monomer; (2) interfere with Aβ(17-36) oligomerization; (3) disrupt a pre-formed Aβ(17-36) protofilament; (4) prevent the growth of Aβ(17-36) protofilament...
October 12, 2017: Journal of Molecular Biology
Adam G Kreutzer, Ryan K Spencer, Kate J McKnelly, Stan Yoo, Imane L Hamza, Patrick J Salveson, James S Nowick
The absence of high-resolution structures of amyloid oligomers constitutes a major gap in our understanding of amyloid diseases. Increasing evidence indicates that oligomers of the β-amyloid peptide Aβ are especially important in the progression of Alzheimer's disease. In many Aβ oligomers, the Aβ monomer components are thought to adopt a β-hairpin conformation. This paper describes the design and study of a macrocyclic β-hairpin peptide derived from Aβ16-36. SDS-PAGE and size exclusion chromatography studies show that the Aβ16-36 β-hairpin peptide assembles in solution to form hexamers, trimers, and dimers...
October 13, 2017: Biochemistry
Tianying Liu, Tyler M Marcinko, Patrick A Kiefer, Richard W Vachet
Amyloid aggregates are associated with several debilitating diseases, and there are numerous efforts to develop small molecule treatments against these diseases. One challenge associated with these efforts is determining protein binding site information for potential therapeutics because amyloid-forming proteins rapidly form oligomers and aggregates, making traditional protein structural analysis techniques challenging. Using β-2-microglobulin (β2m) as a model amyloid-forming protein along with two recently identified small molecule amyloid inhibitors (i...
October 13, 2017: Analytical Chemistry
Christian A Söldner, Heinrich Sticht, Anselm H C Horn
A key player in Alzheimer's disease is the peptide amyloid-beta (Aβ), whose aggregation into small soluble oligomers, protofilaments, and fibrils finally leads to plaque deposits in human brains. The aggregation behavior of Aβ is strongly modulated by the nature and composition of the peptide's environment and by its primary sequence properties. The N-terminal residues of Aβ play an important role, because they are known to change the peptide's aggregation propensity. Since these residues are for the first time completely resolved at the molecular level in a three-fold symmetric fibril structure derived from a patient, we chose that system as template for a systematic investigation of the influence of the N-terminus upon structural stability...
2017: PloS One
Yang Cao, Xuehan Jiang, Wei Han
Early oligomerization during amyloid-β (Aβ) aggregation is essential for Aβ neurotoxicity. Understanding how unstructured Aβs assemble into oligomers, especially those rich in β-sheets, is essential but remains challenging as the assembly process is too transient for experimental characterization and too slow for molecular dynamics simulations. So far, atomic simulations are limited only to studies of either oligomer structures or assembly pathways for short Aβ segments. To overcome the computational challenge, we combine in this study a hybrid-resolution model and adaptive sampling techniques to perform over 2...
October 11, 2017: Journal of Chemical Theory and Computation
Janine Kutzsche, Sarah Schemmert, Markus Tusche, Jörg Neddens, Roland Rabl, Dagmar Jürgens, Oleksandr Brener, Antje Willuweit, Birgit Hutter-Paier, Dieter Willbold
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is associated with the aggregation of the amyloid β protein (Aβ). Aβ oligomers are currently thought to be the major neurotoxic agent responsible for disease development and progression. Thus, their elimination is highly desirable for therapy development. Our therapeutic approach aims at specific and direct elimination of toxic Aβ oligomers by stabilizing Aβ monomers in an aggregation-incompetent conformation. We have proven that our lead compound "D3", an all d-enantiomeric-peptide, specifically eliminates Aβ oligomers in vitro...
October 10, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Michael R Jones, Emilie Mathieu, Christine Dyrager, Simon Faissner, Zavier Vaillancourt, Kyle J Korshavn, Mi Hee Lim, Ayyalusamy Ramamoorthy, V Wee Yong, Shigeki Tsutsui, Peter K Stys, Tim Storr
Alzheimer's disease (AD) is a multifactorial disease that is characterized by the formation of intracellular neurofibrillary tangles and extracellular amyloid-β (Aβ) plaque deposits. Increased oxidative stress, metal ion dysregulation, and the formation of toxic Aβ peptide oligomers are all considered to contribute to the etiology of AD. In this work we have developed a series of ligands that are multi-target-directed in order to address several disease properties. 2-(1-(3-Hydroxypropyl)-1H-1,2,3-triazol-4-yl)phenol (POH), 2-(1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl)phenol (PMorph), and 2-(1-(2-thiomorpholinoethyl)-1H-1,2,3-triazol-4-yl)phenol (PTMorph) have been synthesized and screened for their antioxidant capacity, Cu-binding affinity, interaction with the Aβ peptide and modulation of Aβ peptide aggregation, and the ability to limit Aβ1-42-induced neurotoxicity in human neuronal culture...
August 1, 2017: Chemical Science
Kwame Ofori Affram, Kendall Mitchell, Aviva J Symes
Chronic inflammation mediated by persistent microglial activation is associated with the pathogenesis of neurodegenerative diseases. The mechanisms underlying chronic microglial activation are poorly understood. We have previously shown that anti-inflammatory TGF-β signaling is inhibited in LPS-treated microglia. In this study, we assessed whether different disease-related microglial activators could downregulate TGF-β induction of gene expression. We examined the effects of amyloid β (Aβ) (1-42)- or heat-killed Listeria monocytogenes (HKLM) on the TGF-β-regulated gene expression in primary rat microglia...
October 5, 2017: Journal of Molecular Neuroscience: MN
Emilie Dorard, Stéphanie Chasseigneaux, Lucie Gorisse-Hussonnois, Cédric Broussard, Thierry Pillot, Bernadette Allinquant
Amyloid precursor protein (APP) is cleaved not only to generate the amyloid peptide (Aß), involved in neurodegenerative processes, but can also be metabolized by alpha secretase to produce and release soluble N-terminal APP (sAPPα), which has many properties including the induction of axonal elongation and neuroprotection. The mechanisms underlying the properties of sAPPα are not known. Here, we used proteomic analysis of mouse cortico-hippocampal membranes to identify the neuronal specific alpha3 (α3)-subunit of the plasma membrane enzyme Na, K-ATPase (NKA) as a new binding partner of sAPPα...
October 5, 2017: Molecular Neurobiology
Jacques Hugon, François Mouton-Liger, Julien Dumurgier, Claire Paquet
BACKGROUND: Brain lesions in Alzheimer's disease (AD) are characterized by Aβ accumulation, neurofibrillary tangles, and synaptic and neuronal vanishing. According to the amyloid cascade hypothesis, Aβ1-42 oligomers could trigger a neurotoxic cascade with kinase activation that leads to tau phosphorylation and neurodegeneration. Detrimental pathways that are associated with kinase activation could also be linked to the triggering of direct neuronal death, the production of free radicals, and neuroinflammation...
October 5, 2017: Alzheimer's Research & Therapy
Xuewei Dong, Yunxiang Sun, Guanghong Wei, Ruth Nussinov, Buyong Ma
Alzheimer's disease, a common neurodegenerative disease, is characterized by the aggregation of amyloid-β (Aβ) peptides. The interactions of Aβ with membranes cause changes in membrane morphology and ion permeation, which are responsible for its neurotoxicity and can accelerate fibril growth. However, the Aβ-lipid interactions and how these induce membrane perturbation and disruption at the atomic level and the consequences for the Aβ organization are not entirely understood. Here, we perform multiple atomistic molecular dynamics simulations on three protofibrillar Aβ9-40 trimers...
October 18, 2017: Physical Chemistry Chemical Physics: PCCP
Jiaying Zhao, Fufeng Liu, Chunhui Huang, Jieyi Shentu, Minjun Wang, Chenkai Sun, Liping Chen, Sicheng Yan, Fang Fang, Yuanyuan Wang, Shujun Xu, C Benjamin Naman, Qinwen Wang, Shan He, Wei Cui
The oligomer of β-amyloid (Aβ) is considered the main neurotoxin in Alzheimer's disease (AD). Therefore, the inhibition of the formation of Aβ oligomer could be a target for AD therapy. In this study, with the help of the dot blotting assay and transmission electronic microscopy, it was have discovered that 5-hydroxycyclopenicillone, a cyclopentenone recently isolated from a sponge-associated fungus, effectively reduced the formation of Aβ oligomer from Aβ peptide in vitro. Molecular dynamics simulations suggested hydrophobic interactions between 5-hydroxycyclopenicillone and Aβ peptide, which might prevent the conformational transition and oligomerization of Aβ peptide...
October 1, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
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