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amyloid oligomer

Robert P Weinberg, Vera V Koledova, Hyeari Shin, Jennifer H Park, Yew Ai Tan, Anthony J Sinskey, Ravigadevi Sambanthamurthi, ChoKyun Rha
Alzheimer's disease is a severe neurodegenerative disease characterized by the aggregation of amyloid- β peptide (A β ) into toxic oligomers which activate microglia and astrocytes causing acute neuroinflammation. Multiple studies show that the soluble oligomers of A β 42 are neurotoxic and proinflammatory, whereas the monomers and insoluble fibrils are relatively nontoxic. We show that A β 42 aggregation is inhibited in vitro by oil palm phenolics (OPP), an aqueous extract from the oil palm tree (Elaeis guineensis) ...
2018: International Journal of Alzheimer's Disease
Juan M Zolezzi, Carolina B Lindsay, Felipe G Serrano, Roxana C Ureta, Cristina Theoduloz, Guillermo Schmeda-Hirschmann, Nibaldo C Inestrosa
Soluble amyloid-β (Aβ) oligomers have been recognized as early neurotoxic intermediates with a key role in the synaptic dysfunction observed in Alzheimer's disease (AD). Aβ oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Additionally, the presence of Aβ oligomers is associated with imbalanced intracellular calcium levels and apoptosis in neurons. In this context, we evaluated the effects of three diterpenes (ferruginol, jatrophone, and junicedric acid) that are found in medicinal plants and have several forms of biological activity...
April 10, 2018: Journal of Alzheimer's Disease: JAD
Takuma Maruyama, Harmony Wada, Yoichiro Abe, Takako Niikura
SUMOylation, a post-translational modification of lysine residues by small ubiquitin-like modifier (SUMO) proteins, has been implicated in the pathogenesis of neurodegenerative disorders including Alzheimer's disease (AD), and in neuron- and astrocyte-specific physiological functions. Global SUMOylation is increased in the AD mouse brain in the pre-plaque-forming stage but returns to wild-type levels in the plaque-bearing stage. To clarify the reason for the transient change in SUMOylation, we analyzed the alteration of global SUMOylation induced by AD-associated cytotoxic stimuli in neurons and astrocytes individually...
April 13, 2018: Biochemical and Biophysical Research Communications
Rashik Ahmed, Giuseppe Melacini
The self-association of the amyloid beta (Aβ) peptide into toxic oligomers is implicated in the early events leading to Alzheimer's disease (AD). Blocking the formation of Aβ oligomers and their interactions with the extracellular and cellular environment through small molecules and biopharmaceuticals is therefore a promising preventive strategy for AD. However, given the heterogeneity and transient nature of the Aβ oligomeric species, detailed structural and kinetic characterizations of such oligomers and oligomer:inhibitor complexes have proven to be challenging...
April 16, 2018: Chemical Communications: Chem Comm
Arvi Rauk
β-N-Methylamino-L-alanine (BMAA) is a neurotoxic agent implicated in ALS, Parkinson's and Alzheimer's diseases. It is produced by blue-green algae and could find its way via fish and seafood into the human food supply. Isolation from biological samples yields the compound in monomeric and protein-bound form. It has been suggested that the protein-bound fraction may result from genetic misincorporation into proteins in place of serine. Concomitant misfolding of the mutated proteins may be responsible for the neurological diseases...
April 12, 2018: Journal of Physical Chemistry. B
Sunil Kumar, Anja Henning, Mazin Magzoub, Andrew D Hamilton
The processes associated with the conversion of amyloid beta (Aβ) into intractable amyloid fibers are considered to be pivotal events in Alzheimer's disease (AD). The prevailing hypothesis stipulates that the pre-amyloid oligomers of Aβ are the main culprits associated with the onset and progression of AD, which has prompted efforts to search for therapeutic agents with the ability to inhibit Aβ oligomerization and amyloidogenesis. However, the lack of clinical progress is impeded by the limited structural information about the neurotoxic oligomers...
April 12, 2018: Journal of the American Chemical Society
Yue-Qin Zeng, Yin-Bo Cui, Juan-Hua Gu, Chen Liang, Xin-Fu Zhou
Alzheimer's disease (AD) is pathologically characterized by excessive accumulation of amyloid-beta (Aβ) within extracellular spaces of the brain. Aggregation of Aβ has been shown to trigger oxidative stress, inflammation, and neurotoxicity resulting in cognitive dysfunction. In this study, we use models of cerebral Aβ amyloidosis to investigate anti-amyloidogenic effects of scutellarin in vitro and in vivo. Our results show that scutellarin, through binding to Aβ42, efficiently inhibits oligomerization as well as fibril formation and reduces Aβ oligomer-induced neuronal toxicity in cell line SH-SY5Y...
April 10, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Patrick J Salveson, Sepehr Haerianardakani, Alexander Thuy-Boun, Adam G Kreutzer, James S Nowick
A key challenge in studying the biological and biophysical properties of amyloid-forming peptides is that they assemble to form heterogenous mixtures of soluble oligomers and insoluble fibrils. Photolabile protecting groups have emerged as tools to control the properties of biomolecules with light. Blocking intermolecular hydrogen bonds that stabilize amyloid oligomers provides a general strategy to control the biological and biophysical properties of amyloid-forming peptides. This paper describes the design, synthesis, and characterization of macrocyclic β-hairpin peptides that are derived from amyloidogenic peptides and contain the N-2-nitrobenzyl photolabile protecting group...
April 8, 2018: Journal of the American Chemical Society
Zohra Dhouafli, Manuela Leri, Monica Bucciantini, Massimo Stefani, Hamza Gadhoumi, Borhane Mahjoub, Hichem Ben Jannet, Jérôme Guillard, Moufida Saidani Tounsi, Riadh Ksouri, El Akrem Hayouni
Mounting evidence indicates soluble Aβ42 oligomers as the most toxic species causing neuronal death which leads to the onset and progression of Alzheimer disease (AD). Recently, it has been found that neurotoxic Aβ42 oligomers grow from monomeric species or arise following secondary nucleation by preformed mature fibrils. Thus, the use of natural compounds such as polyphenols to hinder the growth or to remodel Aβ42 fibrils is one of the most promising strategies for AD treatment. In our previous study, we showed that 1, 2, 4-trihydroxynaphthalene-2-O-β-d-glucopyranoside (THNG) inhibits Aβ42 aggregation during the early steps of the aggregation process, inhibits its conformational change to a β-sheet-rich structure, decreases its polymerization, inhibits its fibrillogenisis and reduces oxidative stress and aggregate cytotoxicity...
April 4, 2018: International Journal of Biological Macromolecules
Anoop Rawat, Barun Kumar Maity, Bappaditya Chandra, Sudipta Maiti
Islet amyloid polypeptide (IAPP) is a 37 residue intrinsically disordered protein whose aggregation is associated with Type II diabetes. Like most amyloids, it appears that the intermediate aggregates ("oligomers") of IAPP are more toxic than the mature fibrils, and interaction with the cell membrane is likely to be an integral component of the toxicity. Here we probe the membrane affinity and the conformation of the peptide as a function of its aggregation state. We find that the affinity of the peptide for artificial lipid bilayers is more than 15 times higher in the small oligomeric state (hydrodynamic radius ~ 1...
April 4, 2018: Biochimica et Biophysica Acta
Michael C Owen, Waldemar Kulig, Chetan Poojari, Tomasz Rog, Birgit Strodel
To resolve the contribution of ceramide-containing lipids to the aggregation of the amyloid-β protein into β-sheet rich toxic oligomers, we employed molecular dynamics simulations to study the effect of cholesterol-containing bilayers comprised of POPC (70% POPC, and 30% cholesterol) and physiologically relevant concentrations of sphingomyelin (SM) (30% SM, 40% POPC, and 30% cholesterol), and the GM1 ganglioside (5% GM1, 70% POPC, and 25% cholesterol). The increased bilayer rigidity provided by SM (and to a lesser degree, GM1) reduced the interactions between the SM-enriched bilayer and the N-terminus of Aβ42 (and also residues Ser26, Asn27, and Lys28), which facilitated the formation of a β-sheet in the normally disordered N-terminal region...
April 4, 2018: Biochimica et Biophysica Acta
Laia Montoliu-Gaya, Sandra D Mulder, Maaike A C Herrebout, Johannes C Baayen, Sandra Villegas, Robert Veerhuis
An imbalance between production and clearance of soluble amyloid-β (Aβ) initiates the pathological process in sporadic Alzheimer's disease (AD). Aβ-specific antibodies seemed promising as therapeutic option in AD mouse models. In patients, however, vascular side-effects and Aβ-antibody complex-induced microglial and/or perivascular macrophage inflammatory responses were encountered. To prevent inflammatory reactions, we designed a single chain variable fragment (scFv-h3D6), based on monoclonal antibody bapineuzumab (mAb-h3D6), but lacking the Fc region...
April 3, 2018: Molecular and Cellular Neurosciences
Valentina Oliveri, Stefania Zimbone, Maria Laura Giuffrida, Francesco Bellia, Marianna Flora Tomasello, Graziella Vecchio
Although fibrillar amyloid beta peptide (Aβ) aggregates are one of the major hallmarks of Alzheimer's disease, increasing evidence suggests that soluble Aβ oligomers are the primary toxic species. Targeting the oligomeric species could represent an effective strategy to interfere with Aβ toxicity. In this work, the biological properties of 5[4-(6-O-β-cyclodextrin)-phenyl],10,15,20-tri(4-hydroxyphenyl)-porphyrin and its zinc complex were tested, as new molecules that interact with Aβ and effectively prevent its cytotoxicity...
April 6, 2018: Chemistry: a European Journal
Michał Maj, Justin P Lomont, Kacie L Rich, Ariel M Alperstein, Martin T Zanni
Human islet amyloid polypeptide (hIAPP) aggregates into fibrils through oligomers that have been postulated to contain α-helices as well as β-sheets. We employ a site-specific isotope labeling strategy that is capable of detecting changes in dihedral angles when used in conjunction with 2D IR spectroscopy. The method is analogous to the chemical shift index used in NMR spectroscopy for assigning protein secondary structure. We introduce isotope labels at two neighbouring residues, which results in an increased intensity and positive frequency shift if those residues are α-helical versus a negative frequency shift in β-sheets and turns...
January 14, 2018: Chemical Science
Yinhui Li, Di Xu, Anyang Sun, See-Lok Ho, Chung-Yan Poon, Hei-Nga Chan, Olivia T W Ng, Ken K L Yung, Hui Yan, Hung-Wing Li, Man Shing Wong
Alzheimer's disease (AD) is the most prevalent but still incurable neurodegenerative form of dementia. Early diagnosis and intervention are crucial for delaying the onset and progression of the disease. We herein report a novel fluoro-substituted cyanine, F-SLOH, which exhibits good Aβ oligomer selectivity with a high binding affinity, attributed to the synergistic effect of strong π-π stacking and intermolecular CH···O and CH···F interactions. The selectivity towards the Aβ oligomers in the brain was ascertained by in vitro labelling on tissue sections and in vivo labelling through the systemic administration of F-SLOH in 7 month APP/PS1 double transgenic (Tg) and APP/PS1/Tau triple Tg mouse models...
December 1, 2017: Chemical Science
Igor A Iashchishyn, Marina Gruden, Roman Moskalenko, Tatiana Davydova, Chao Wang, Robert D E Sewell, Ludmilla A Morozova-Roche
Amyloid formation and neuroinflammation are major features of Alzheimer's disease pathology. Proinflammatory mediator S100A9 was shown to act as a link between the amyloid and neuroin-flammatory cascades in Alzheimer's disease, leading together with Aβ to plaque formation, neu-ronal loss and memory impairment. In order to examine if S100A9 alone in its native and amy-loid states can induce neuronal stress and memory impairment, we have administered S100A9 species intranasally to aged mice. Single and sequential immunohistochemistry and passive avoidance behavioral test were conducted to evaluate the consequences...
April 4, 2018: ACS Chemical Neuroscience
Melissa Birol, Sunil Kumar, Elizabeth Rhoades, Andrew D Miranker
Peptide mediated gain-of-toxic function is central to pathology in Alzheimer's, Parkinson's and diabetes. In each system, self-assembly into oligomers is observed and can also result in poration of artificial membranes. Structural requirements for poration and the relationship of structure to cytotoxicity is unaddressed. Here we focus on islet amyloid polypeptide (IAPP) mediated loss-of-insulin secreting cells in patients with diabetes. Newly developed methods enable structure-function enquiry to focus on intracellular oligomers composed of hundreds of IAPP...
April 3, 2018: Nature Communications
Judith Silverman, Ebrima Gibbs, Xubiao Peng, Kris Martens, Claudia Balducci, Jing Wang, Masoud Yousefi, Catherine M Cowan, Guillaume Lamour, Sarah Louadi, Yuxin Ban, Jerome Robert, Sophie Stukas, Gianluigi Forloni, Ging-Yuek R Hsiung, Steven S Plotkin, Cheryl L Wellington, Neil R Cashman
Oligomers of Amyloid-β (AβO) are deemed key in synaptotoxicity and amyloid seeding of Alzheimer's disease (AD). However, the heterogeneous and dynamic nature of AβO, and inadequate markers for AβO subtypes, have stymied effective AβO identification and therapeutic targeting in vivo. We identified an AβO-subclass epitope defined by differential solvent orientation of the lysine 28 sidechain in a constrained loop of serine-asparagine-lysine (cSNK), rarely displayed in molecular dynamics simulations of monomer and fibril ensembles...
April 4, 2018: ACS Chemical Neuroscience
Heyun Yang, Tingting Hou, Wei Wang, Yumin Luo, Feng Yan, Jianping Jia
Alzheimer's disease (AD) and cerebrovascular disease often coexist. However, it is difficult to determine how chronic cerebral hypoperfusion affects the metabolism of amyloid-β peptides (Aβ) in a living patient with AD. Thus, we developed an animal model of this condition, using transgenic mice (PS1V97L) and right common carotid artery ligation to create chronic cerebral hypoperfusion. The metabolic processes associated with amyloid-β peptide (Aβ) were observed and evaluated in this PS1V97L plus hypoperfusion model...
2018: Journal of Alzheimer's Disease: JAD
Ting-Ting Hou, He-Yun Yang, Wei Wang, Qiao-Qi Wu, Yuan-Ruhua Tian, Jian-Ping Jia
Abnormal amyloid-β (Aβ) aggregates are a striking feature of Alzheimer's disease (AD), and Aβ oligomers have been proven to be crucial in the pathology of AD. Any intervention targeting the generation or aggregation of Aβ can be expected to be useful in AD treatment. Oxidative stress and inflammation are common pathological changes in AD that are involved in the generation and aggregation of Aβ. In the present study, 6-month-old PS1V97L transgenic (Tg) mice were treated with sulforaphane, an antioxidant, for 4 months, and this treatment significantly inhibited the generation and aggregation of Aβ...
2018: Journal of Alzheimer's Disease: JAD
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