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https://www.readbyqxmd.com/read/28927263/molecular-and-cellular-basis-of-neurodegeneration-in-alzheimer-s-disease
#1
Sangyun Jeong
The most common form of senile dementia is Alzheimer's disease (AD), which is characterized by the extracellular deposition of amyloid beta-peptide (Abeta) plaques and the intracellular formation of neurofibrillary tangles (NFTs) in the cerebral cortex. Tau abnormalities are commonly observed in many neurodegenerative diseases including AD, Parkinson's disease, and Pick's disease. Interestingly, tau-mediated formation of NFTs in AD brains shows better correlation with cognitive impairment than Abeta plaque accumulation; pathological tau alone is sufficient to elicit frontotemporal dementia, but it does not cause AD...
September 20, 2017: Molecules and Cells
https://www.readbyqxmd.com/read/28922846/different-complicated-brain-pathologies-in-monozygotic-twins-with-gerstmann-str%C3%A3-ussler-scheinker-disease
#2
Hiroyuki Honda, Kensuke Sasaki, Hiroshi Takashima, Daisuke Mori, Sachiko Koyama, Satoshi O Suzuki, Toru Iwaki
Gerstmann-Sträussler-Scheinker disease (GSS) is an autosomal, dominantly inherited prion disease. In this study, we present different complicated brain pathologies determined postmortem of monozygotic GSS twin sisters. Case 1 showed cerebellar ataxia at the age of 58 years, and died at 66 years. Case 2 became symptomatic at the age of 75 years, and died at 79 years. There was a 17-year difference in the age of onset between the twins. Postmortem examination revealed numerous prion protein (PrP) plaques in the brains of both cases...
October 1, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/28922400/protein-folding-misfolding-and-aggregation-the-importance-of-two-electron-stabilizing-interactions
#3
Andrzej Stanisław Cieplak
Proteins associated with neurodegenerative diseases are highly pleiomorphic and may adopt an all-α-helical fold in one environment, assemble into all-β-sheet or collapse into a coil in another, and rapidly polymerize in yet another one via divergent aggregation pathways that yield broad diversity of aggregates' morphology. A thorough understanding of this behaviour may be necessary to develop a treatment for Alzheimer's and related disorders. Unfortunately, our present comprehension of folding and misfolding is limited for want of a physicochemical theory of protein secondary and tertiary structure...
2017: PloS One
https://www.readbyqxmd.com/read/28922156/soluble-oligomers-require-a-ganglioside-to-trigger-neuronal-calcium-overload
#4
Roberta Cascella, Elisa Evangelisti, Alessandra Bigi, Matteo Becatti, Claudia Fiorillo, Massimo Stefani, Fabrizio Chiti, Cristina Cecchi
An altered distribution of membrane gangliosides (GM), including GM1, has recently been reported in the brains of Alzheimer's disease (AD) patients. Moreover, amyloid-positive synaptosomes obtained from AD brains were found to contain high-density GM1 clusters, suggesting a pathological significance of GM1 increase at presynaptic neuritic terminals in AD. Here, we show that membrane GM1 specifically recruits small soluble oligomers of the 42-residue form of amyloid-β peptide (Aβ42), with intracellular flux of Ca2+ ions in primary rat hippocampal neurons and in human neuroblastoma cells...
September 8, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28919235/alzheimer-s-disease-like-paired-helical-filament-assembly-from-truncated-tau-protein-is-independent-of-disulphide-cross-linking
#5
Youssra K Al-Hilaly, Saskia J Pollack, Devkee Vadukul, Francesca Citossi, Janet E Rickard, Michael Simpson, John M D Storey, Charles R Harrington, Claude M Wischik, Louise C Serpell
Alzheimer's disease is characterised by the self-assembly of tau and amyloid β proteins into oligomers and fibrils. Tau protein assembles into paired helical filaments (PHFs) that constitute the neurofibrillary tangles observed in neuronal cell bodies in individuals with Alzheimer's disease. The mechanism of initiation of tau assembly into PHFs is not well understood. Here we report that a truncated 95-amino acid tau fragment (corresponding to residues 297-391 of full-length tau) assembles into PHF-like fibrils in vitro without the need for other additives to initiate or template the process...
September 15, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28917837/memantine-inhibits-%C3%AE-amyloid-aggregation-and-disassembles-preformed-%C3%AE-amyloid-aggregates
#6
Kaori Ito, Mitsuhiro Makino, Keiko Okado, Taisuke Tomita
Memantine, an uncompetitive glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, is widely used as a medication for the treatment of Alzheimer's disease (AD). We previously reported that chronic treatment of AD with memantine reduces the amount of insoluble β-amyloid (Aβ) and soluble Aβ oligomers in animal models of AD. The mechanisms by which memantine reduces Aβ levels in the brain were evaluated by determining the effect of memantine on Aβ aggregation using thioflavin T and transmission electron microscopy...
September 13, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28917147/combined-in-silico-approaches-for-the-identification-of-novel-inhibitors-of-human-islet-amyloid-polypeptide-hiapp-fibrillation
#7
Palak Patel, Krupali Parmar, Vivek K Vyas, Dhaval Patel, Mili Das
Human islet amyloid polypeptide (hIAPP) is a natively unfolded polypeptide hormone of glucose metabolism, which is co-secreted with insulin by the β-cells of the pancreas. In patients with type 2 diabetes, IAPP forms amyloid fibrils because of diabetes-associated β-cells dysfunction and increasing fibrillation, in turn, lead to failure of secretory function of β-cells. This provides a target for the discovery of small organic molecules against protein aggregation diseases. However, the binding mechanism of these molecules with monomers, oligomers and fibrils to inhibit fibrillation is still an open question...
September 6, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28912710/key-aging-associated-alterations-in-primary-microglia-response-to-beta-amyloid-stimulation
#8
Cláudia Caldeira, Carolina Cunha, Ana R Vaz, Ana S Falcão, Andreia Barateiro, Elsa Seixas, Adelaide Fernandes, Dora Brites
Alzheimer's disease (AD) is characterized by a progressive cognitive decline and believed to be driven by the self-aggregation of amyloid-β (Aβ) peptide into oligomers and fibrils that accumulate as senile plaques. It is widely accepted that microglia-mediated inflammation is a significant contributor to disease pathogenesis; however, different microglia phenotypes were identified along AD progression and excessive Aβ production was shown to dysregulate cell function. As so, the contribution of microglia to AD pathogenesis remains to be elucidated...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28912603/novel-insight-into-streptozotocin-induced-diabetic-rats-from-the-protein-misfolding-perspective
#9
Edgar Leyva-García, Reyna Lara-Martínez, Liborio Morán-Zanabria, Cristina Revilla-Monsalve, Luis Felipe Jiménez-García, Norma Oviedo, Chiharu Murata, Eulalia Garrido-Magaña, Nelly F Altamirano-Bustamante, Myriam M Altamirano-Bustamante
Protein folding is a process of self-assembly defined by the sequence of the amino acids of the protein involved. Additionally, proteins tend to unfold, misfold and aggregate due to both intrinsic and extrinsic causes. Human islet amyloid polypeptide (hIAPP) aggregation is an early step in diabetes mellitus. However, the aggregation of rat IAPP (rIAPP) remains an open question. Adult female Sprague-Dawley rats weighing 150-250 g were divided into two groups. The experimental group (streptozotocin [STZ]) (n = 21) received an intraperitoneal injection of a single dose of 40 mg/kg STZ...
September 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28911813/functional-dynamics-in-cyclic-nucleotide-signaling-and-amyloid-inhibition
#10
REVIEW
Bryan VanSchouwen, Rashik Ahmed, Julijana Milojevic, Giuseppe Melacini
It is now established that understanding the molecular basis of biological function requires atomic resolution maps of both structure and dynamics. Here, we review several illustrative examples of functional dynamics selected from our work on cyclic nucleotide signaling and amyloid inhibition. Although fundamentally diverse, a central aspect common to both fields is that function can only be rationalized by considering dynamic equilibria between distinct states of the accessible free energy landscape. The dynamic exchange between ground and excited states of signaling proteins is essential to explain auto-inhibition and allosteric activation...
September 11, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28906069/distribution-of-amyloid-like-and-oligomeric-species-from-protein-aggregation-kinetics
#11
Alexandra Silva, Bruno Almeida, Joana Sofia Fraga, Pablo Taboada, Pedro Miguel Martins, Sandra Ribeiro
Amyloid fibrils and soluble oligomers are two types of protein aggregates associated with neurodegeneration. Classic therapeutic strategies try to prevent the nucleation and spread of amyloid fibrils, whilst diffusible oligomers have emerged as promising drug targets affecting downstream pathogenic processes. We developed a generic protein aggregation model and validate it against measured compositions of fibrillar and non-fibrillar assemblies of ataxin-3, a protein implicated in Machado-Joseph disease. The derived analytic rate-law equations can be used to (i) identify the presence of parallel aggregation pathways and (ii) estimate the critical sizes of amyloid fibrils...
September 14, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28905328/lessons-learned-from-protein-aggregation-toward-technological-and-biomedical-applications
#12
REVIEW
César L Avila, Silvina Chaves, Sergio B Socias, Esteban Vera-Pingitore, Florencia González-Lizárraga, Cecilia Vera, Diego Ploper, Rosana Chehín
The close relationship between protein aggregation and neurodegenerative diseases has been the driving force behind the renewed interest in a field where biophysics, neurobiology and nanotechnology converge in the study of the aggregate state. On one hand, knowledge of the molecular principles that govern the processes of protein aggregation has a direct impact on the design of new drugs for high-incidence pathologies that currently can only be treated palliatively. On the other hand, exploiting the benefits of protein aggregation in the design of new nanomaterials could have a strong impact on biotechnology...
September 13, 2017: Biophysical Reviews
https://www.readbyqxmd.com/read/28904227/peptide-probes-detect-misfolded-transthyretin-oligomers-in-plasma-of-hereditary-amyloidosis-patients
#13
Joseph D Schonhoft, Cecilia Monteiro, Lars Plate, Yvonne S Eisele, John M Kelly, Daniel Boland, Christopher G Parker, Benjamin F Cravatt, Sergio Teruya, Stephen Helmke, Mathew Maurer, John Berk, Yoshiki Sekijima, Marta Novais, Teresa Coelho, Evan T Powers, Jeffery W Kelly
Increasing evidence supports the hypothesis that soluble misfolded protein assemblies contribute to the degeneration of postmitotic tissue in amyloid diseases. However, there is a dearth of reliable nonantibody-based probes for selectively detecting oligomeric aggregate structures circulating in plasma or deposited in tissues, making it difficult to scrutinize this hypothesis in patients. Hence, understanding the structure-proteotoxicity relationships driving amyloid diseases remains challenging, hampering the development of early diagnostic and novel treatment strategies...
September 13, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28900141/dianxianning-improved-amyloid-%C3%AE-induced-pathological-characteristics-partially-through-daf-2-daf-16-insulin-like-pathway-in-transgenic-c-elegans
#14
Dejuan Zhi, Dong Wang, Wenqi Yang, Ziyun Duan, Shuqian Zhu, Juan Dong, Na Wang, Ningbo Wang, Dongqing Fei, Zhanxin Zhang, Xin Wang, Meizhu Wang, Hongyu Li
Dianxianning (DXN) is a traditional Chinese formula, and has been approved in China for treating epilepsy since 1996. Here anti-Alzheimer's disease activity of DXN has been reported. DXN improved AD-like symptoms of paralysis and 5-HT sensitivity of transgenic Aβ1-42 C. elegans. In worms, DXN significantly increased Aβ monomers and decreased the toxic Aβ oligomers, thus reducing Aβ toxicity. DXN significantly suppressed the expression of hsp-16.2 induced by juglone, and up-regulated sod-3 expression. These results indicated that DXN increased stress resistance and protected C...
September 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28893064/aqueous-raft-synthesis-of-glycopolymers-for-determination-of-saccharide-structure-and-concentration-effects-on-amyloid-%C3%AE-aggregation
#15
Pradipta Kumar Das, Dexter N Dean, April L Fogel, Fei Liu, Brooks A Abel, Charles L McCormick, Eugenia Kharlampieva, Vijayaraghavan Rangachari, Sarah E Morgan
GM1 ganglioside is known to promote amyloid-β (Aβ) peptide aggregation in Alzheimer's disease. The roles of the individual saccharides and their distribution in this process are not understood. Acrylamide-based glycomonomers with either β-D-glucose or β-D-galactose pendant groups were synthesized to mimic the stereochemistry of saccharides present in GM1 and characterized via 1H NMR and electrospray ionization mass spectrometry. Glycopolymers of different molecular weights were synthesized by aqueous reversible addition fragmentation chain transfer (aRAFT) polymerization and characterized by NMR and GPC...
September 11, 2017: Biomacromolecules
https://www.readbyqxmd.com/read/28892583/fluorescent-probe-dcvj-shows-high-sensitivity-for-characterization-of-amyloid-beta-peptide-early-in-the-lag-phase
#16
Sureshbabu Nagarajan, Lisa Jill Lapidus
The aggregation of intrinsically disordered and misfolded proteins in the form of oligomers and fibrils plays a crucial role in a number of neuro and non-neurodegenerative diseases. Currently, most probes and biophysical techniques that detect and characterize fibrils to high resolution fail to show sensitivity and binding for oligomers. Here we show 9-(dicyano-vinyl) julolidine (DCVJ), a class of molecular rotor, binds Aβ early aggregates and reports on the kinetics as well as packing of oligomer formation...
September 11, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28881033/the-conformational-epitope-for-a-new-a%C3%AE-42-protofibril-selective-antibody-partially-overlaps-with-the-peptide-n-terminal-region
#17
Benjamin A Colvin, Victoria A Rogers, Joshua A Kulas, Elizabeth A Ridgway, Fatima S Amtashar, Colin K Combs, Michael R Nichols
Aggregation and accumulation of amyloid-β peptide (Aβ) is a key component of Alzheimer's disease (AD). While monomeric Aβ appears to be benign, oligomers adopt a biologically detrimental structure. These soluble structures can be detected in AD brain tissue by antibodies that demonstrate selectivity for aggregated Aβ. Protofibrils are a subset of soluble oligomeric Aβ species and are described as small (<100 nm) curvilinear assemblies enriched in β-sheet structure. Our own in vitro studies demonstrate that microglial cells are much more sensitive to soluble Aβ42 protofibrils compared to Aβ42 monomer or insoluble Aβ42 fibrils...
September 7, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28878984/a-mix-and-click-method-to-measure-amyloid-%C3%AE-concentration-with-sub-micromolar-sensitivity
#18
Christine Xue, Yoon Kyung Lee, Joyce Tran, Dennis Chang, Zhefeng Guo
Aggregation of amyloid-β (Aβ) protein plays a central role in Alzheimer's disease. Because protein aggregation is a concentration-dependent process, rigorous investigations require accurate concentration measurements. Owing to the high aggregation propensity of Aβ protein, working solutions of Aβ are typically in the low micromolar range. Therefore, an ideal Aβ quantification method requires high sensitivity without sacrificing speed and accuracy. Absorbance at 280 nm is frequently used to measure Aβ concentration, but the sensitivity is low with only one tyrosine and no tryptophan residues in the Aβ sequence...
August 2017: Royal Society Open Science
https://www.readbyqxmd.com/read/28872299/comparison-of-%C3%AE-synuclein-fibril-inhibition-by-four-different-amyloid-inhibitors
#19
Narendra Nath Jha, Rakesh Kumar, Rajlaxmi Panigrahi, Ambuja Navalkar, Dhiman Ghosh, Shruti Sahay, Mrityunjoy Mondal, Ashutosh Kumar, Samir K Maji
Aggregation of α-synuclein (α-Syn) into toxic oligomers and fibrils leads to Parkinson's disease (PD) pathogenesis. Molecules that can inhibit the fibrillization and oligomerization of α-Syn have potential therapeutic value. Here, we studied four selective amyloid inhibitors: Dopamine (Dopa), Amphotericin-B (Amph), Epigallocatechingallate (EGCG) and Quinacrinedihydrochloride (Quin) for their effect on oligomerization, fibrillization and preformed fibrils of α-Syn. The aggregation kinetics of α-Syn using ThT fluorescence and conformational transition by circular dichroism (CD) in the presence and absence of these four compounds suggest that, except Quin, remaining three molecules inhibit α-Syn aggregation in concentration dependent manner...
September 5, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28871125/hiv-1-matrix-protein-p17-misfolding-forms-toxic-amyloidogenic-assemblies-that-induce-neurocognitive-disorders
#20
Yasmin Zeinolabediny, Francesca Caccuri, Laura Colombo, Federica Morelli, Margherita Romeo, Alessandro Rossi, Silvia Schiarea, Carlotta Ciaramelli, Cristina Airoldi, Ria Weston, Liu Donghui, Jerzy Krupinski, Rubén Corpas, Elisa García-Lara, Sara Sarroca, Coral Sanfeliu, Mark Slevin, Arnaldo Caruso, Mario Salmona, Luisa Diomede
Human immunodeficiency virus type-1 (HIV-1)-associated neurocognitive disorder (HAND) remains an important neurological manifestation that adversely affects a patient's quality of life. HIV-1 matrix protein p17 (p17) has been detected in autoptic brain tissue of HAND individuals who presented early with severe AIDS encephalopathy. We hypothesised that the ability of p17 to misfold may result in the generation of toxic assemblies in the brain and may be relevant for HAND pathogenesis. A multidisciplinary integrated approach has been applied to determine the ability of p17 to form soluble amyloidogenic assemblies in vitro...
September 4, 2017: Scientific Reports
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