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Amyloidogenicity and toxicity of the reverse and scrambled variants of amyloid-? 1-42.

ABSTRACT: ?-amyloid 1-42 (A?1-42) is a self-assembling peptide that goes through many conformational and morphological changes before forming the fibrils that are deposited in extracellular plaques characteristic of Alzheimer's disease. The link between A?1-42 structure and toxicity is of major interest, in particular, the neurotoxic potential of oligomeric species. Many studies utilise reversed (A?42-1) and scrambled (A?S) forms of amyloid-? as control peptides. Here, using circular dichroism, thioflavin T fluorescence and transmission electron microscopy, we reveal that both control peptides self-assemble to form fibres within 24 h. However, oligomeric A? reduces cell survival of hippocampal neurons, while A?42-1 and A?s have reduced effect on cellular health, which may arise from their ability to assemble rapidly to form protofibrils and fibrils.

SUBMITTER: Vadukul DM

PROVIDER: S-EPMC5363225 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Amyloidogenicity and toxicity of the reverse and scrambled variants of amyloid-β 1-42.

Vadukul Devkee M DM Gbajumo Oyinkansola O Marshall Karen E KE Serpell Louise C LC

FEBS letters 20170228 5

β-amyloid 1-42 (Aβ1-42) is a self-assembling peptide that goes through many conformational and morphological changes before forming the fibrils that are deposited in extracellular plaques characteristic of Alzheimer's disease. The link between Aβ1-42 structure and toxicity is of major interest, in particular, the neurotoxic potential of oligomeric species. Many studies utilise reversed (Aβ42-1) and scrambled (AβS) forms of amyloid-β as control peptides. Here, using circular dichroism, thioflavin ...[more]

PMID: 28185264

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Nanospectral data of amyloid beta 1-42 and scrambled amyloid beta 1-42

Project description:Two carrier-free peptides were synthesized and used in experiments: amyloid beta 42 (DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA), and a scrambled variant with the same chemical constituency as amyloid beta 42 (AIAEGDSHVLKEGAYMEIFDVQGHVFGGKIFRVVDLGSHNVA). To perform blockade current measurements, first, the sub-nanopore was wetted by immersion in de-gassed 250 mM NaCl electrolyte for 1-3 days. Subsequently, to measure the blockade current, a transmembrane voltage bias (< 700 mV) was applied to the reservoir relative to the ground in the channel using Ag/AgCl electrodes and the corresponding pore current was measured using either an Axopatch 700B or an Axopatch 200B amplifier with an open bandwidth. The actual bandwidth was inferred from the rise-time to a sharp (10 ps rise-time) input pulse to be about 75 kHz to 100 kHz, depending on the amplifier and the feedback. The analog data were digitized by a 16-bit DigiData 1550B data acquisition system (DAQ, Molecular Devices, Sunnyvale, CA) at a sampling rate of 500 kS/s and recorded in 3 minute-long acquisition windows. A total of 12 Axon binary files (ABF) were collected for amyloid beta 42, and 71 ABF files for scrambled amyloid beta 42.

2022-06-30 | MSV000089779 | MassIVE

The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity.

Project description:Amyloid beta 42 (Abeta42) is the principal trigger of neurodegeneration during Alzheimer's disease (AD). However, the etiology of its noxious cellular effects remains elusive. In a combinatory genetic and proteomic approach using a yeast model to study aspects of intracellular Abeta42 toxicity, we here identify the HSP40 family member Ydj1, the yeast orthologue of human DnaJA1, as a crucial factor in Abeta42-mediated cell death. We demonstrate that Ydj1/DnaJA1 physically interacts with Abeta42 (in yeast and mouse), stabilizes Abeta42 oligomers, and mediates their translocation to mitochondria. Consequently, deletion of YDJ1 strongly reduces co-purification of Abeta42 with mitochondria and prevents Abeta42-induced mitochondria-dependent cell death. Consistently, purified DnaJ chaperone delays Abeta42 fibrillization in vitro, and heterologous expression of human DnaJA1 induces formation of Abeta42 oligomers and their deleterious translocation to mitochondria in vivo. Finally, downregulation of the Ydj1 fly homologue, Droj2, improves stress resistance, mitochondrial morphology, and memory performance in a Drosophila melanogaster AD model. These data reveal an unexpected and detrimental role for specific HSP40s in promoting hallmarks of Abeta42 toxicity.

| S-EPMC9081910 | biostudies-literature

The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity

Project description:Amyloid beta 42 (Abeta42) is the principal trigger of neurodegeneration during Alzheimer's disease (AD). However, the etiology of its noxious cellular effects remains elusive. In a combinatory genetic and proteomic approach using a yeast model to study aspects of intracellular Abeta42 toxicity, we here identify the HSP40 family member Ydj1, the yeast orthologue of human DnaJA1, as a crucial factor in Abeta42-mediated cell death. We demonstrate that Ydj1/DnaJA1 physically interacts with Abeta42 (in yeast and mouse), stabilizes Abeta42 oligomers, and mediates their translocation to mitochondria. Consequently, deletion of YDJ1 strongly reduces co-purification of Abeta42 with mitochondria and prevents Abeta42-induced mitochondria-dependent cell death. Consistently, purified DnaJ chaperone delays Abeta42 fibrillization in vitro, and heterologous expression of human DnaJA1 induces formation of Abeta42 oligomers and their deleterious translocation to mitochondria in vivo. Finally, downregulation of the Ydj1 fly homologue, Droj2, improves stress resistance, mitochondrial morphology and memory performance in a Drosophila melanogaster AD model. These data reveal an unexpected and detrimental role for specific HSP40s in promoting hallmarks of Abeta42 toxicity.

| S-SCDT-EMM-2021-13952 | biostudies-other

Hypochlorite-induced oxidation promotes aggregation and reduces toxicity of amyloid beta 1-42.

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Heme oxygenase-1 protects against Alzheimer's amyloid-β(1-42)-induced toxicity via carbon monoxide production.

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| S-EPMC4454163 | biostudies-literature

C-Terminal Fragment, Aβ<sub>39-42</sub>-Based Tetrapeptides Mitigates Amyloid-β Aggregation-Induced Toxicity.

Project description:Since the introduction of acetyl cholinesterase inhibitors as the first approved drugs by the US Food and Drug Administration for Alzheimer's disease (AD) in clinics, less than satisfactory success in the design of anti-AD agents has impelled the scientists to also focus toward inhibition of Aβ aggregation. Considering the specific binding of fragments for their parent peptide, herein, we synthesized more than 40 new peptides based on a C-terminus tetrapeptide fragment of Aβ1-42. Initial screening by MTT cell viability assay and supportive results by ThT fluorescence assay led us to identify a tetrapeptide showing complete inhibition for Aβ1-42 aggregation. Peptide 20 displayed 100% cell viability at 20 μM concentration, while at lower concentrations of 10 and 2 μM 76.6 and 70% of cells were viable. Peptide 20 was found to restrict the conformational transition of Aβ1-42 peptide toward β-sheet structure. Inhibitory activity of tetrapeptide 20 was further evidenced by the absence of Aβ1-42 aggregates in electron microscopy. Peptide 20 and other significantly active tetrapeptide analogues could prove imperative in the future design of anti-AD agents.

| S-EPMC6645473 | biostudies-literature

Amyloid-beta 42 adsorption following serial tube transfer.

Project description:IntroductionCerebrospinal fluid (CSF) amyloid-beta 38 (A?38), 40 (A?40), 42 (A?42) and total tau (T-tau) are finding increasing utility as biomarkers of Alzheimer's disease (AD). The purpose of this study was to determine whether measured CSF biomarker concentrations were affected by transfer of CSF between tubes, and whether addition of a non-ionic surfactant mitigates any observed effects.MethodsAD and control CSF was transferred consecutively between polypropylene tubes. A? peptides and T-tau were measured with and without addition of Tween 20 (0.05%).ResultsMeasured concentrations of A?42 decreased by approximately 25% with each consecutive transfer. Measured concentrations of A?38 and A?40 were also observed to decrease significantly with each consecutive transfer (approximately 16% loss per transfer). Measured concentrations of T-tau also decreased significantly, but at much smaller magnitude than the A? peptides (approximately 4% loss per transfer). The addition of Tween 20 mitigated this effect in all samples.ConclusionsConsecutive CSF transfer between tubes has a significant impact on the measured concentration of all A? peptides, and significant effect of lesser magnitude on T-tau. This would be sufficient to alter biomarker ratios enough to mislead diagnosis. The introduction of Tween 20 at the initial aliquoting stage was observed to significantly mitigate this effect.

| S-EPMC4059346 | biostudies-literature

Human membrane metallo-endopeptidase-like protein degrades both beta-amyloid 42 and beta-amyloid 40.

Project description:Beta-amyloid (Abeta) degrading endopeptidases are thought to protect against Alzheimer's disease (AD) and are potentially therapeutic. Of particular interest are endopeptidases that are blocked by thiorphan and phosphoramidon (T/P), as these inhibitors rapidly induce Abeta deposition in rodents. Neprilysin (NEP) is the best known target of T/P; however neprilysin knockout results in only modest Abeta increases insufficient to induce deposition. Therefore, other endopeptidases targeted by T/P must be critical for Abeta catabolism. Another candidate is the T/P sensitive membrane metallo-endopeptidase-like protein (MMEL), a close homolog of neprilysin. The endopeptidase properties of beta and gamma splice forms of human MMEL were determined in HEK293T cells transduced with the human cDNAs for the two splice forms; this showed degradation of both Abeta(42) and Abeta(40) by hMMEL-beta but not hMMEL-gamma. hMMEL-beta activity was found at the extracellular surface with no significant secreted activity. hMMEL-gamma was not expressed at the extracellular surface. Finally, it was found that hMMEL cleaves Abeta near the alpha-secretase site (producing Abeta(1-17)>>Abeta(1-16)). These data establish hMMEL as a mediator of Abeta catabolism and raise the possibility of its involvement in the etiology of AD and as a target for intervention.

| S-EPMC2597530 | biostudies-literature

Misfolded amyloid-β-42 impairs the endosomal-lysosomal pathway.

Project description:Misfolding and aggregation of proteins is strongly linked to several neurodegenerative diseases, but how such species bring about their cytotoxic actions remains poorly understood. Here we used specifically-designed optical reporter probes and live fluorescence imaging in primary hippocampal neurons to characterise the mechanism by which prefibrillar, oligomeric forms of the Alzheimer's-associated peptide, Aβ42, exert their detrimental effects. We used a pH-sensitive reporter, Aβ42-CypHer, to track Aβ internalisation in real-time, demonstrating that oligomers are rapidly taken up into cells in a dynamin-dependent manner, and trafficked via the endo-lysosomal pathway resulting in accumulation in lysosomes. In contrast, a non-assembling variant of Aβ42 (vAβ42) assayed in the same way is not internalised. Tracking ovalbumin uptake into cells using CypHer or Alexa Fluor tags shows that preincubation with Aβ42 disrupts protein uptake. Our results identify a potential mechanism by which amyloidogenic aggregates impair cellular function through disruption of the endosomal-lysosomal pathway.

| S-EPMC7658065 | biostudies-literature

3D structure of Alzheimer's amyloid-beta(1-42) fibrils.

Project description:Alzheimer's disease is the most fatal neurodegenerative disorder wherein the process of amyloid-beta (Abeta) amyloidogenesis appears causative. Here, we present the 3D structure of the fibrils comprising Abeta(1-42), which was obtained by using hydrogen-bonding constraints from quenched hydrogen/deuterium-exchange NMR, side-chain packing constraints from pairwise mutagenesis studies, and parallel, in-register beta-sheet arrangement from previous solid-state NMR studies. Although residues 1-17 are disordered, residues 18-42 form a beta-strand-turn-beta-strand motif that contains two intermolecular, parallel, in-register beta-sheets that are formed by residues 18-26 (beta1) and 31-42 (beta2). At least two molecules of Abeta(1-42) are required to achieve the repeating structure of a protofilament. Intermolecular side-chain contacts are formed between the odd-numbered residues of strand beta1 of the nth molecule and the even-numbered residues of strand beta2 of the (n - 1)th molecule. This interaction pattern leads to partially unpaired beta-strands at the fibrillar ends, which explains the sequence selectivity, the cooperativity, and the apparent unidirectionality of Abeta fibril growth. It also provides a structural basis for fibrillization inhibitors.

| S-EPMC1297669 | biostudies-literature

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