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Mechanistic and environmental control of the prevalence and lifetime of amyloid oligomers.

ABSTRACT: Amyloid fibrils are self-assembled protein aggregates implicated in a number of human diseases. Fragmentation-dominated models for the self-assembly of amyloid fibrils have had important successes in explaining the kinetics of amyloid fibril formation but predict fibril length distributions that do not match experiments. Here we resolve this inconsistency using a combination of experimental kinetic measurements and computer simulations. We provide evidence for a structural transition that occurs at a critical fibril mass concentration, or CFC, above which fragmentation of fibrils is suppressed. Our simulations predict the formation of distinct fibril length distributions above and below the CFC, which we confirm by electron microscopy. These results point to a new picture of amyloid fibril growth in which structural transitions that occur during self-assembly have strong effects on the final population of aggregate species with small, and potentially cytotoxic, oligomers dominating for long periods of time at protein concentrations below the CFC.

SUBMITTER: Morris RJ

PROVIDER: S-EPMC3796876 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Mechanistic and environmental control of the prevalence and lifetime of amyloid oligomers.

Morris Ryan J RJ Eden Kym K Yarwood Reuben R Jourdain Line L Allen Rosalind J RJ Allen Rosalind J RJ Macphee Cait E CE

Nature communications 20130101

Amyloid fibrils are self-assembled protein aggregates implicated in a number of human diseases. Fragmentation-dominated models for the self-assembly of amyloid fibrils have had important successes in explaining the kinetics of amyloid fibril formation but predict fibril length distributions that do not match experiments. Here we resolve this inconsistency using a combination of experimental kinetic measurements and computer simulations. We provide evidence for a structural transition that occurs ...[more]

PMID: 23695685

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Project description:UnlabelledMicroglial dysfunction is increasingly recognized as a key contributor to the pathogenesis of Alzheimer's disease (AD). Environmental enrichment (EE) is well documented to enhance neuronal form and function, but almost nothing is known about whether and how it alters the brain's innate immune system. Here we found that prolonged exposure of naive wild-type mice to EE significantly altered microglial density and branching complexity in the dentate gyrus of hippocampus. In wild-type mice injected intraventricularly with soluble Aβ oligomers (oAβ) from hAPP-expressing cultured cells, EE prevented several morphological features of microglial inflammation and consistently prevented oAβ-mediated mRNA changes in multiple inflammatory genes both in vivo and in primary microglia cultured from the mice. Microdialysis in behaving mice confirmed that EE normalized increases in the extracellular levels of the key cytokines (CCL3, CCL4, TNFα) identified by the mRNA analysis. Moreover, EE prevented the changes in microglial gene expression caused by ventricular injection of oAβ extracted directly from AD cerebral cortex. We conclude that EE potently alters the form and function of microglia in a way that prevents their inflammatory response to human oAβ, suggesting that prolonged environmental enrichment could protect against AD by modulating the brain's innate immune system.Significance statementEnvironmental enrichment (EE) is a potential therapy to delay Alzheimer's disease (AD). Microglial inflammation is associated with the progression of AD, but the influence of EE on microglial inflammation is unclear. Here we systematically applied in vivo methods to show that EE alters microglia in the dentate gyrus under physiological conditions and robustly prevents microglial inflammation induced by human Aβ oligomers, as shown by neutralized microglial inflammatory morphology, mRNA changes, and brain interstitial fluid cytokine levels. Our findings suggest that EE alters the innate immune system and could serve as a therapeutic approach to AD and provide new targets for drug discovery. Further, we propose that the therapeutic benefits of EE could extend to other neurodegenerative diseases involving microglial inflammation.

Dataset Information

Mechanistic and environmental control of the prevalence and lifetime of amyloid oligomers.

Publications

Mechanistic and environmental control of the prevalence and lifetime of amyloid oligomers.

Similar Datasets

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