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Amyloid oligomers

Ganesh M Mohite, Rakesh Kumar, Rajlaxmi Panigrahi, Ambuja Navalkar, Nitu Singh, Debalina Datta, Surabhi Mehra, Soumik Ray, Laxmikant G Gadhe, Subhadeep Das, Namrata Singh, Debdeep Chatterjee, Ashutosh Kumar, Samir K Maji
The involvement of α-synuclein (α-Syn) amyloid formation in Parkinson's disease (PD) pathogenesis is supported by the discovery of α-Syn gene (SNCA) mutations linked with familial PD, which are known to modulate the oligomerization and aggregation of α-Syn. Recently, the A53V mutation has been discovered, which leads to the late-onset PD. In the present study, we characterized for the first time the biophysical properties including the aggregation propensities, toxicity of aggregated species and membrane binding capability of A53V along with all familial mutations at A53 position...
May 17, 2018: Biochemistry
Marco Luciani, Luca Troncone, Federica Del Monte
Cardiac amyloidosis (CA) comprises a heterogeneous group of medical conditions affecting the myocardium. It presents with proteinaceous infiltration with variable degrees of severity, prevalence and evolution. Despite this heterogeneity, erroneous protein folding is the common pathophysiologic process, yielding the formation of a single misfolded protein (monomer) that progressively evolves and ultimately forms amyloid fibers. Additionally, by seeding out from the organs of origin, intermediates called oligomers metastasize and restart the process...
May 17, 2018: Acta Pharmacologica Sinica
Nasimudeen R Jabir, Fayaz Rahman Khan, Shams Tabrez
Alzheimer's disease (AD) is a progressive irreversible neurodegenerative disorder characterized by excessive deposition of β-amyloid (Aβ) oligomers, and neurofibrillary tangles (NFTs), comprising of hyperphosphorylated tau proteins. The cholinergic system has been suggested as the earliest and most affected molecular mechanism that describes AD pathophysiology. Moreover, cholinesterase inhibitors (ChEIs) are the potential class of drugs that can amplify cholinergic activity to improve cognition and global performance and reduce psychiatric and behavioral disturbances...
May 16, 2018: CNS Neuroscience & Therapeutics
Anna Beatriz Wreden, Luiza Fernandes, Mirian Kelley, Antônio Pereira-Neves, Caroline S Moreira, David R da Rocha, Fernando L Palhano
Protein aggregation is a hallmark of several degenerative diseases, including Alzheimer's disease, Parkinson's disease and familial amyloidosis (Finnish type) (FAF). A method to isolate and detect amyloids is desired for the diagnosis of amyloid diseases. Here, we report the synthesis of pentameric thiophene amyloid ligand (p-FTAA) linked to agarose resin for selective purification of amyloid aggregates produced in vitro and in vivo. Using amyloid fibrils produced in vitro from alpha-synuclein, gelsolin and Aβ1-40 and gelsolin amyloid aggregates extracted from tissue homogenates of a mouse model of FAF, we observed that p-FTAA resin was able to pull down amyloid aggregates...
May 15, 2018: ACS Chemical Neuroscience
Ewelina Lipiec, David Perez-Guaita, Janina Kaderli, Bayden Wood, Renato Zenobi
The aggregation pathways of neurodegenerative peptides determine the disease etiology and their better understanding can lead to strategies for early disease treatment. Previous research has allowed modelling of hypothetic aggregation pathways. However, their direct experimental observation has been elusive due to methodological limitations. Here we demonstrate that nanoscale chemical mapping by Tip-Enhanced Raman Spectroscopy of single amyloid fibrils at various stages of aggregation captures the fibril formation process...
May 11, 2018: Angewandte Chemie
Justin Ng, Roger D Kamm, Thorsten Wohland, Rachel S Kraut
The amyloid-beta (Aβ) peptide, commonly found in elevated levels in the brains of patients with Alzheimer's disease (AD), and in the cerebrospinal fluid of individuals presenting mild cognitive impairment (MCI), is thought to be one of the major factors resulting in the onset of AD. Although observed and studied at the molecular level for several decades, the exact disease pathology of AD is still not totally clear. One way in which Aβ is thought to affect neurons is by influencing cell membrane fluidity, which could result in abnormal synaptic or signaling function...
May 7, 2018: Journal of Molecular Biology
Bonnie J Berry, Alec S T Smith, Christopher J Long, Candace C Martin, James J Hickman
Alzheimer's disease (AD) is characterized by slow, progressive neurodegeneration leading to severe neurological impairment, but current drug development efforts are limited by the lack of robust, human-based disease models. Amyloid-β (Aβ) is known to play an integral role in AD progression as it has been shown to interfere with neurological function. However, studies into AD pathology commonly apply Aβ to neurons for short durations at non-physiological concentrations to induce an exaggerated dysfunctional phenotype...
May 10, 2018: ACS Chemical Neuroscience
Samuel A Kotler, Ayyalusamy Ramamoorthy
Soluble amyloid-β (Aβ) oligomers have become a focal point in the study of Alzheimer's disease due to their ability to elicit cytotoxicity. A number of recent studies have concentrated on the structural characterization of soluble Aβ oligomers to gain insight into their mechanism of toxicity. Consequently, providing reproducible protocols for the preparation of such oligomers is of utmost importance. The method presented in this chapter details a protocol for preparing an Aβ oligomer, with a primarily disordered secondary structure, without the need for chemical modification or amino acid substitution...
2018: Methods in Molecular Biology
Jean-Marie Ruysschaert, Vincent Raussens
Attenuated total reflection FTIR (ATR-FTIR) has been used for decades to study protein secondary structures. More recently, it reveals also to be an exquisite and sensitive tool to study and discriminate amyloid aggregates. Based on the analysis of specific spectral features of β-sheet structures, we present here a detailed protocol to differentiate oligomers vs. fibrils. This protocol, applicable to all amyloid proteins, demonstrates the power of this inexpensive, rapid, and low protein material-demanding method...
2018: Methods in Molecular Biology
James Brown, Mathew H Horrocks
The aberrant aggregation of normally soluble proteins into amyloid fibrils is the pathological hallmark of several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Understanding this process will be key to developing both diagnostic and therapeutic approaches for neurodegenerative diseases. Recent advances in biophysical techniques, coupled with kinetic analyses have enabled a thorough description of the key molecular steps involved in protein aggregation. In this review, we discuss these advances and how they have been applied to study the ability of one such protein, α-Synuclein, to form neurotoxic oligomers...
May 5, 2018: Seminars in Cell & Developmental Biology
Cristina Cantarutti, Gijo Raj, Federico Fogolari, Sofia Giorgetti, Alessandra Corazza, Vittorio Bellotti, Panče Naumov, Gennaro Esposito
Protein fibrillation is involved in many serious diseases, and protein oligomers are proved to be precursors of amyloid fibrils. NMR and QCMD experiments allowed us to establish that the interaction between citrate-stabilized gold nanoparticles and a paradigmatic amyloidogenic protein, β2-microglobulin, is able to interfere with protein association into oligomers.
May 8, 2018: Chemical Communications: Chem Comm
Jieling Qin, Dong Gyu Jo, Misuk Cho, Youngkwan Lee
Amyloid-beta oligomers (AβΟ) are considered to be reliable biomarkers for the diagnosis of Alzheimer' disease (AD), and the cellular prion protein (PrPC ) is identified as a receptor for AβO. We demonstrated a label and antibody-free electrochemical biosensor for the selective detection of AβO using an electrically conductive poly(pyrrole-2-carboxylic acid) (PPyCOOH) linking agent and PrPC receptor. In the fabrication of the biosensor, each step was characterized by electrochemical impedance spectroscopy and cyclic voltammetry...
May 1, 2018: Biosensors & Bioelectronics
Jie Zhou, Lingchang Meng, Weiran Ye, Qiaolei Wang, Shizhen Geng, Chong Sun
Alzheimer's disease (AD) considered as the third health "killer" has seriously threatened the health of the elderly. However, the modern diagnostic strategies of AD present several disadvantages: the low accuracy and specificity resulting in some false-negative diagnoses, and the poor sensitivity leading to a delayed treatment. In view of this situation, a enzyme-free and target-triggered signal amplification strategy, based on graphene oxide (GO) and entropy-driven strand displacement reaction (ESDR) principle, was proposed...
August 31, 2018: Analytica Chimica Acta
Yujie Chen, Zihan Chen, Yunxiang Sun, Jiangtao Lei, Guanghong Wei
The aggregation of amyloid-β (Aβ), which involves the formation of small oligomers and mature fibrils, has received considerable attention in the past few decades due to its close link with Alzheimer's disease (AD). The inhibition of β-sheet formation has been considered as the primary therapeutic strategy for AD. In this respect, graphene oxide (GO) has gained significant attention because of its high solubility, good biocompatibility and inhibitory effect on the aggregation of Aβ and the 33-42 fragment (Aβ33-42)...
May 4, 2018: Nanoscale
Montserrat Serra-Batiste, James Tolchard, Fabrice Giusti, Manuela Zoonens, Natàlia Carulla
We have recently reported on the preparation of a membrane-associated β -barrel Pore-Forming Aβ42 Oligomer (β PFO Aβ 42 ). It corresponds to a stable and homogeneous Aβ42 oligomer that inserts into lipid bilayers as a well-defined pore and adopts a specific structure with characteristics of a β-barrel arrangement. As a follow-up of this work, we aim to establish β PFO Aβ 42 's relevance in Alzheimer's disease (AD). However, β PFO Aβ 42 is formed under dodecyl phosphocholine (DPC) micelle conditions-intended to mimic the hydrophobic environment of membranes-which are dynamic...
2018: Frontiers in Molecular Biosciences
Matthew A Downey, Maxwell J Giammona, Christian A Lang, Steven K Buratto, Ambuj Singh, Michael T Bowers
Alzheimer's disease (AD) is rapidly reaching epidemic status among a burgeoning aging population. Much evidence suggests the toxicity of this amyloid disease is most influenced by the formation of soluble oligomeric forms of amyloid β-protein, particularly the 42-residue alloform (Aβ42). Developing potential therapeutics in a directed, streamlined approach to treating this disease is necessary. Here we utilize the joint pharmacophore space (JPS) model to design a new molecule [AC0107] incorporating structural characteristics of known Aβ inhibitors, blood-brain barrier permeability, and limited toxicity...
April 30, 2018: Journal of the American Society for Mass Spectrometry
Manuel Menendez-Gonzalez, Huber S Padilla-Zambrano, Gabriel Alvarez, Estibaliz Capetillo-Zarate, Cristina Tomas-Zapico, Agustin Costa
Although immunotherapies against the amyloid-β (Aβ) peptide tried so date failed to prove sufficient clinical benefit, Aβ still remains the main target in Alzheimer's disease (AD). This article aims to show the rationale of a new therapeutic strategy: clearing Aβ from the CSF continuously (the "CSF-sink" therapeutic strategy). First, we describe the physiologic mechanisms of Aβ clearance and the resulting AD pathology when these mechanisms are altered. Then, we review the experiences with peripheral Aβ-immunotherapy and discuss the related hypothesis of the mechanism of action of "peripheral sink...
2018: Frontiers in Aging Neuroscience
Abhik Sen, Thomas J Nelson, Daniel L Alkon, Jarin Hongpaisan
Oxidative stress and amyloid-β (Aβ) oligomers have been implicated in Alzheimer's disease (AD). The growth and maintenance of neuronal networks are influenced by brain derived neurotrophic factor (BDNF) expression, which is promoted by protein kinase C epsilon (PKCɛ). We investigated the reciprocal interaction among oxidative stress, Aβ, and PKCɛ levels and subsequent PKCɛ-dependent MnSOD and BDNF expression in hippocampal pyramidal neurons. Reduced levels of PKCɛ, MnSOD, and BDNF and an increased level of Aβ were also found in hippocampal neurons from autopsy-confirmed AD patients...
April 25, 2018: Journal of Alzheimer's Disease: JAD
Karishma Bhasne, Sanjana Sebastian, Neha Jain, Samrat Mukhopadhyay
Amyloidogenic intrinsically disordered proteins, α-synuclein and tau are linked to Parkinson's disease and Alzheimer's disease, respectively. A body of evidences suggests that α-synuclein and tau, both present in the presynaptic nerve terminals, co-aggregate in many neurological ailments. The molecular mechanism of α-synuclein-tau hetero-assembly is poorly understood. Here we show that amyloid formation is synergistically facilitated by heterotypic association mediated by binding-induced misfolding of both α-synuclein and tau K18...
April 25, 2018: Journal of Molecular Biology
Yen-Ting Lai, Hirotsugu Ogi, Kentaro Noi, Fumihito Kato
Unlike previous in-vitro measurements where Aβ aggregation was studied in bulk solutions, we detect the structure change of the Aβ aggregate on the surface of a wireless quartz-crystal-microbalance biosensor, which resembles more closely the aggregation process on the cell membrane. Using a 58-MHz quartz crystal, we monitored changes in the viscoelastic properties of the aggregate formed on the quartz surface from monomers to oligomers and then to fibrils, involving up to the 7th overtone mode (406 MHz). With atomic-force-microscopy observations, we found significant stiffness increase as well as thinning of the protein layer during the structure change from oligomer to fibrils at ~20 h, which indicates that the stiffness of the fibril is much higher...
April 26, 2018: Langmuir: the ACS Journal of Surfaces and Colloids
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