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Neurodegenerative diseases

Metabolite-mediated misfolding

Nature Reviews Drug Discovery volume 3, page 390 (2004)Cite this article

One possibility is that modification by abnormal metabolites causes wild-type Aβ to misfold. Recently established links between Alzheimer's disease, high cholesterol levels and inflammation prompted a team of investigators led by Jeffery Kelly to focus on the Aβ-modifying potential of metabolites that form through the reaction of cholesterol with ozone, which is generated during inflammation.

A key property of these cholesterol metabolites is that they possess an aldehyde group, which could form a bond with amines in Aβ. Attachment of cholesterol metabolites would markedly increase the hydrophobicity of Aβ, potentially increasing the likelihood of misfolding. To assess this possibility, several cholesterol metabolites were individually incubated with Aβ. Two — dubbed compounds 1 and 2 — caused a concentration-dependent increase in the rate of amyloidogenesis and were shown to be present in human brains.

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References

ORIGINAL RESEARCH PAPER

  1. Zhang, Q. et al. Metabolite-initiated protein misfolding may trigger Alzheimer's disease. Proc. Natl Acad. Sci. USA 101, 4752–4757 (2004)

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FURTHER READING

  1. Barnham, K. J., Masters, C. L. & Bush, A. I. Neurodegenerative diseases and oxidative stress. Nature Rev. Drug Discov. 3, 205–214 (2004)

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Authors
  1. Suzanne Farley
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Farley, S. Metabolite-mediated misfolding. Nat Rev Drug Discov 3, 390 (2004). https://doi.org/10.1038/nrd1391

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