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Multicolor time-stamp reveals the dynamics and toxicity of amyloid deposition.

ABSTRACT: The pathogenic role of amyloid plaques in Alzheimer's disease (AD) remains controversial given poor correlation between plaque burden and cognitive status in clinicopathological studies. However, these postmortem studies cannot provide information about the dynamics of plaque expansion and consequent neurotoxicity. We developed a novel method for plaque birth-dating and growth analysis using sequential labeling with amyloid-binding dyes and postmortem quantitative confocal imaging. Using this technique in an AD mouse model, we find that plaques grow gradually over months with growth slowing in older animals. The degree of neuritic dystrophy correlates with the speed and extent of plaque enlargement suggesting a causal relationship. Surprisingly, new plaques induce a disproportionately large area of neuritic dystrophy whereas with older plaques the degree of injury plateaus despite continued growth. Our results suggest that the kinetics of amyloid deposition is a critical determinant of neurotoxicity, which is completely overlooked by traditional measures of plaque burden.

SUBMITTER: Condello C

PROVIDER: S-EPMC3216507 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Multicolor time-stamp reveals the dynamics and toxicity of amyloid deposition.

Condello Carlo C Schain Aaron A Grutzendler Jaime J

Scientific reports 20110621

The pathogenic role of amyloid plaques in Alzheimer's disease (AD) remains controversial given poor correlation between plaque burden and cognitive status in clinicopathological studies. However, these postmortem studies cannot provide information about the dynamics of plaque expansion and consequent neurotoxicity. We developed a novel method for plaque birth-dating and growth analysis using sequential labeling with amyloid-binding dyes and postmortem quantitative confocal imaging. Using this te ...[more]

PMID: 22355538

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Project description:Cytotoxicity is a commonly used in vitro endpoint for evaluating chemical toxicity. In support of the U.S. Tox21 screening program, the cytotoxicity of ~10K chemicals was interrogated at 0, 8, 16, 24, 32, & 40 hours of exposure in a concentration dependent fashion in two cell lines (HEK293, HepG2) using two multiplexed, real-time assay technologies. One technology measures the metabolic activity of cells (i.e., cell viability, glo) while the other evaluates cell membrane integrity (i.e., cell death, flor). Using glo technology, more actives and greater temporal variations were seen in HEK293 cells, while results for the flor technology were more similar across the two cell types. Chemicals were grouped into classes based on their cytotoxicity kinetics profiles and these classes were evaluated for their associations with activity in the Tox21 nuclear receptor and stress response pathway assays. Some pathways, such as the activation of H2AX, were associated with the fast-responding cytotoxicity classes, while others, such as activation of TP53, were associated with the slow-responding cytotoxicity classes. By clustering pathways based on their degree of association to the different cytotoxicity kinetics labels, we identified clusters of pathways where active chemicals presented similar kinetics of cytotoxicity. Such linkages could be due to shared underlying biological processes between pathways, for example, activation of H2AX and heat shock factor. Others involving nuclear receptor activity are likely due to shared chemical structures rather than pathway level interactions. Based on the linkage between androgen receptor antagonism and Nrf2 activity, we surmise that a subclass of androgen receptor antagonists cause cytotoxicity via oxidative stress that is associated with Nrf2 activation. In summary, the real-time cytotoxicity screen provides informative chemical cytotoxicity kinetics data related to their cytotoxicity mechanisms, and with our analysis, it is possible to formulate mechanism-based hypotheses on the cytotoxic properties of the tested chemicals.

Project description:Deposition of insoluble amyloid plaques is frequently associated with a large variety of neurodegenerative diseases. However, data collected in the last decade have suggested that the neurotoxic action is exerted by prefibrillar, soluble assemblies of amyloid-forming proteins and peptides. The scarcity of structural data available for both amyloid-like fibrils and soluble oligomers is a major limitation for the definition of the molecular mechanisms linked to the onset of these diseases. Recently, the structural characterization of GNNQQNY and other peptides has shown a general feature of amyloid-like fibers, the so-called steric zipper motif. However, very little is known still about the prefibrillar oligomeric forms. By using replica exchange molecular dynamics we carried out extensive analyses of the properties of several small and medium GNNQQNY aggregates arranged through the steric zipper motif. Our data show that the assembly formed by two sheets, each made of two strands, arranged as in the crystalline states are highly unstable. Conformational free energy surfaces indicate that the instability of the model can be ascribed to the high reactivity of edge backbone hydrogen bonding donors/acceptors. On the other hand, data on larger models show that steric zipper interactions may keep small oligomeric forms in a stable state. These models simultaneously display two peculiar structural motifs: a tightly packed steric zipper interface and a large number of potentially reactive exposed strands. The presence of highly reactive groups on these assemblies likely generates two distinct evolutions. On one side the reactive groups quickly lead, through self-association, to the formation of ordered fibrils, on the other they may interfere with several cellular components thereby generating toxic effects. In this scenario, fiber formation propensity and toxicity of oligomeric states are two different manifestations of the same property: the hyper-reactivity of the exposed strands.

Dataset Information

Multicolor time-stamp reveals the dynamics and toxicity of amyloid deposition.

Publications

Multicolor time-stamp reveals the dynamics and toxicity of amyloid deposition.

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