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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

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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.

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The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity

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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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Using Drosophila to identify naturally occurring genetic modifiers of amyloid beta 42- and tau-induced toxicity.

Project description:Alzheimer's disease is characterized by 2 pathological proteins, amyloid beta 42 and tau. The majority of Alzheimer's disease cases in the population are sporadic and late-onset Alzheimer's disease, which exhibits high levels of heritability. While several genetic risk factors for late-onset Alzheimer's disease have been identified and replicated in independent studies, including the ApoE ε4 allele, the great majority of the heritability of late-onset Alzheimer's disease remains unexplained, likely due to the aggregate effects of a very large number of genes with small effect size, as well as to biases in sample collection and statistical approaches. Here, we present an unbiased forward genetic screen in Drosophila looking for naturally occurring modifiers of amyloid beta 42- and tau-induced ommatidial degeneration. Our results identify 14 significant SNPs, which map to 12 potential genes in 8 unique genomic regions. Our hits that are significant after genome-wide correction identify genes involved in neuronal development, signal transduction, and organismal development. Looking more broadly at suggestive hits (P < 10-5), we see significant enrichment in genes associated with neurogenesis, development, and growth as well as significant enrichment in genes whose orthologs have been identified as significantly or suggestively associated with Alzheimer's disease in human GWAS studies. These latter genes include ones whose orthologs are in close proximity to regions in the human genome that are associated with Alzheimer's disease, but where a causal gene has not been identified. Together, our results illustrate the potential for complementary and convergent evidence provided through multitrait GWAS in Drosophila to supplement and inform human studies, helping to identify the remaining heritability and novel modifiers of complex diseases.

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Amyloid-beta 42 adsorption following serial tube transfer.

Project description:IntroductionCerebrospinal fluid (CSF) amyloid-beta 38 (Aβ38), 40 (Aβ40), 42 (Aβ42) 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. Aβ peptides and T-tau were measured with and without addition of Tween 20 (0.05%).ResultsMeasured concentrations of Aβ42 decreased by approximately 25% with each consecutive transfer. Measured concentrations of Aβ38 and Aβ40 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 Aβ 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 Aβ 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

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