Misfolded protein oligomers induce an increase of intracellular Ca2+ causing an escalation of reactive oxidative species (original) (raw)
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Journal of Biological …, 2005
Increasing evidence suggests that amyloid peptides associated with a variety of degenerative diseases induce neurotoxicity in their intermediate oligomeric state, rather than as monomers or fibrils. To test this hypothesis and investigate the possible involvement of Ca 2+ signaling disruptions in amyloid-induced cytotoxicity, we made homogeneous preparations of disease-related amyloids (Aß, Prion, IAPP, polyglutamine, and lysozyme) in various aggregation states and tested their actions on fluo-3-loaded SH-SY5Y cells. Application of oligomeric forms of all amyloids tested (0.6-6 µg ml-1) rapidly (~ 5s) elevated intracellular Ca 2+ , whereas equivalent amounts of monomers and fibrils did not. Ca 2+ signals evoked by Aß42 oligomers persisted after depletion of intracellular Ca 2+ stores, and small signals remained in Ca 2+-free medium; indicating contributions from both extracellular and intracellular Ca 2+ sources. The increased membrane permeability to Ca 2+ cannot be attributed to activation of endogenous Ca 2+ channels, because responses were unaffected by the potent Ca 2+-channel blocker cobalt (20 µM). Instead, observations that Aß42 and other oligomers caused rapid cellular leakage of anionic fluorescent dyes point to a generalized increase in membrane permeability. The resulting unregulated flux of ions and molecules may provide a common mechanism for oligomer-mediated toxicity in many amyloidogenic diseases, with dysregulation of Ca 2+ ions playing a crucial role owing to their strong trans-membrane concentration gradient and involvement in cell dysfunction and death.
Amino Acids, 2010
A neuropathological characteristic of Alzheimer's disease is the extracellular accumulation of amyloid beta peptide (Ab) in neuritic plaques. Recent evidences suggested that soluble Ab oligomers are the predominant neurotoxic species for neurons. Thus, considerable attention has been paid to discriminate the cytotoxic pathways of Ab pre-fibrillar aggregates and mature fibrils. We showed that the mechanisms by which Ab oligomers and fibrils generated reactive oxygen species differ in terms of site of production and kinetics, suggesting the involvement of different intra/extracellular pathways.
Scientific Reports, 2016
The conversion of peptides or proteins from their soluble native states into intractable amyloid deposits is associated with a wide range of human disorders. Misfolded protein oligomers formed during the process of aggregation have been identified as the primary pathogenic agents in many such conditions. Here, we show the existence of a quantitative relationship between the degree of binding to neuronal cells of different types of oligomers formed from a model protein, HypF-N, and the GM1 content of the plasma membranes. In addition, remarkably similar behavior is observed for oligomers of the Aβ 42 peptide associated with Alzheimer's disease. Further analysis has revealed the existence of a linear correlation between the level of the influx of Ca 2+ across neuronal membranes that triggers cellular damage, and the fraction of oligomeric species bound to the membrane. Our findings indicate that the susceptibility of neuronal cells to different types of misfolded oligomeric assemblies is directly related to the extent of binding of such oligomers to the cellular membrane.
Oxidative Medicine and Cellular Longevity, 2018
Reactive oxygen species (ROS) generated after exposure to ionizing radiation and toxic peptides, in mitochondrial metabolism and during aging contribute to damage of cell’s structural and functional components and can lead to diseases. Monomers and small oligomers of amyloid beta (Aβ) peptide, players in Alzheimer’s disease, are recently suggested to be involved in damaging of neurons, instead of extracellular Aβ plaques. We demonstrate that externally applied disaggregated Aβ1–42 peptide interacts preferentially with acidic compartments (lysosomes). We compared standard cell cultivation (21% O2) to more physiological cell cultivation (5% O2). Cells did not exhibit a dramatic increase in ROS and change in glutathione level upon 4 μM Aβ peptide treatment, whereas exposure to 2 Gy X-rays increased ROS and changed glutathione level and ATP concentration. The occurrence of the 4977 bp deletion in mtDNA and significant protein carbonylation were specific effects of IR and more pronounced...
Amyloid oligomer neurotoxicity, calcium dysregulation, and lipid rafts
International journal of Alzheimer's disease, 2011
Amyloid proteins constitute a chemically heterogeneous group of proteins, which share some biophysical and biological characteristics, the principal of which are the high propensity to acquire an incorrect folding and the tendency to aggregate. A number of diseases are associated with misfolding and aggregation of proteins, although only in some of them-most notably Alzheimer's disease (AD) and transmissible spongiform encephalopathies (TSEs)-a pathogenetic link with misfolded proteins is now widely recognized. Lipid rafts (LRs) have been involved in the pathophysiology of diseases associated with protein misfolding at several levels, including aggregation of misfolded proteins, amyloidogenic processing, and neurotoxicity. Among the pathogenic misfolded proteins, the AD-related protein amyloid β (Aβ) is by far the most studied protein, and a large body of evidence has been gathered on the role played by LRs in Aβ pathogenicity. However, significant amount of data has also been ...
Lipid rafts are primary mediators of amyloid oxidative attack on plasma membrane
Journal of Molecular Medicine, 2010
Increasing evidence indicates that cell surfaces are early interaction sites for Aβ-derived diffusible ligands (ADDLs) and neurons in Alzheimer's disease (AD) pathogenesis. Our previous data showed significant oxidative damage at the plasma membrane in fibroblasts from familial AD patients with enhanced Aβ production. Here, we report that lipid rafts, ordered membrane microdomains, are chronic mediators of Aβ-induced lipid peroxidation in SH-SY5Y human neuroblastoma cells overexpressing amyloid precursor protein (APPwt) and APPV717G genes and in fibroblasts bearing the APPV717I gene mutation.
Journal of Neuroscience, 2013
Oligomeric forms of -amyloid (A) peptides associated with Alzheimer's disease (AD) disrupt cellular Ca 2ϩ regulation by liberating Ca 2ϩ into the cytosol from both extracellular and intracellular sources. We elucidated the actions of intracellular A 42 by imaging Ca 2ϩ responses to injections of A oligomers into Xenopus oocytes. Two types of signal were observed: (1) local, "channel-like" transients dependent on extracellular Ca 2ϩ influx, which resembled signals from amlyoid pores formed by extracellular application of oligomers; and (2) local transients and global Ca 2ϩ waves, resembling Ca 2ϩ puffs and waves mediated by inositol trisphosphate (IP 3). The latter responses were suppressed by antagonists of the IP 3 receptor (caffeine and heparin), pretreatment with the G i/o-protein inhibitor pertussis toxin, and pretreatment with lithium to deplete membrane inositol lipids. We show that G-protein-mediated stimulation of IP 3 production and consequent liberation of Ca 2ϩ from the endoplasmic reticulum by intracellular A oligomers is cytotoxic, potentially representing a novel pathological mechanism in AD which may be further exacerbated by AD-linked mutations in presenilins to promote opening of IP 3 receptor/channels.
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2012
Oxidative stress is associated with several major ailments. However, it is only recently that the developments in our molecular level understanding of the consequences of oxidative stress in modifying the chemical structures of biomolecules, lipids in particular, are beginning to open new emerging insights into the significance of oxidative stress in providing mechanistic insights into the etiologies of these diseases. In this brief review we will first discuss the role of lipid oxidation in controlling the membrane binding of cytochrome c, a key protein in the control of apoptosis. We then present an overview of the impact of oxidized phospholipids on the biophysical properties of lipid bilayers and continue to discuss, how these altered properties can account for the observed enhancement of formation of intermediate state oligomers by cytotoxic amyloid forming peptides associated with pathological conditions as well as host defense peptides of innate immunity. In the third part, we will discuss how the targeting of oxidized phospholipids by i) pathology associated peptides and ii) host defense peptides can readily explain the observed clinical correlations associating Alzheimer's and Parkinson's diseases with increased risk for type 2 diabetes and age-related macular degeneration, and the apparent protective effect of Alzheimer's and Parkinson's diseases from some cancers, as well as the inverse, apparent protection by cancer from Alzheimer's and Parkinson's diseases. This article is part of a Special Issue entitled: Oxidized phospholipids-Their properties and interactions with proteins.