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Evidence for altered cholesterol metabolism in Huntington's disease post mortem brain tissue

Journal Article


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Abstract


  • Aims

    Cholesterol plays an essential role in membrane structure and function, being especially important in the brain. Alteration of brain cholesterol synthesis and metabolism has been demonstrated in several Huntington's disease (HD) mouse and cell models; however, less is known about these alterations in human tissue. This study aimed to identify alterations to cholesterol synthetic and metabolic pathways in human HD brain tissue.

    Methods

    A broad range of cholesterol synthetic precursors, metabolites and oxidation products were measured by gas chromatography-tandem mass spectrometry in five regions of human post mortem HD brain and compared with age- and sex-matched control tissues. The level of enzymes that regulate cholesterol homeostasis, cholesterol 24-hydroxylase and delta(24)-sterol reductase were investigated by Western blotting and qPCR in putamen.

    Results

    The most significant changes were localized to the putamen, where a 60% decrease in 24(S)-hydroxycholesterol, 30% increase in cholesterol and 100–200% increase in synthetic precursors (lathosterol, zymosterol and desmosterol) was detected. The enzymes cholesterol 24-hydroxylase and delta(24)-sterol reductase were also significantly decreased in HD putamen as compared with control tissues. Free radical-generated cholesterol oxidation products 7-keto cholesterol and 7β-hydroxycholesterol were also increased by 50–70% in HD putamen.

    Conclusion

    Human HD brain has significantly decreased cholesterol metabolism and disrupted cholesterol homeostasis. Our data also indicate that lipid oxidative stress accompanies HD pathology.

Authors


  •   Kreilaus, Fabian (external author)
  •   Spiro, Adena S. (external author)
  •   McLean, Catriona A. (external author)
  •   Garner, Brett
  •   Jenner, Andrew M. (external author)

Publication Date


  • 2016

Citation


  • Kreilaus, F., Spiro, A. S., McLean, C. A., Garner, B. & Jenner, A. M. (2016). Evidence for altered cholesterol metabolism in Huntington's disease post mortem brain tissue. Neuropathology and Applied Neurobiology, 42 535-546.

Scopus Eid


  • 2-s2.0-84951089389

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1629&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/607

Number Of Pages


  • 11

Start Page


  • 535

End Page


  • 546

Volume


  • 42

Abstract


  • Aims

    Cholesterol plays an essential role in membrane structure and function, being especially important in the brain. Alteration of brain cholesterol synthesis and metabolism has been demonstrated in several Huntington's disease (HD) mouse and cell models; however, less is known about these alterations in human tissue. This study aimed to identify alterations to cholesterol synthetic and metabolic pathways in human HD brain tissue.

    Methods

    A broad range of cholesterol synthetic precursors, metabolites and oxidation products were measured by gas chromatography-tandem mass spectrometry in five regions of human post mortem HD brain and compared with age- and sex-matched control tissues. The level of enzymes that regulate cholesterol homeostasis, cholesterol 24-hydroxylase and delta(24)-sterol reductase were investigated by Western blotting and qPCR in putamen.

    Results

    The most significant changes were localized to the putamen, where a 60% decrease in 24(S)-hydroxycholesterol, 30% increase in cholesterol and 100–200% increase in synthetic precursors (lathosterol, zymosterol and desmosterol) was detected. The enzymes cholesterol 24-hydroxylase and delta(24)-sterol reductase were also significantly decreased in HD putamen as compared with control tissues. Free radical-generated cholesterol oxidation products 7-keto cholesterol and 7β-hydroxycholesterol were also increased by 50–70% in HD putamen.

    Conclusion

    Human HD brain has significantly decreased cholesterol metabolism and disrupted cholesterol homeostasis. Our data also indicate that lipid oxidative stress accompanies HD pathology.

Authors


  •   Kreilaus, Fabian (external author)
  •   Spiro, Adena S. (external author)
  •   McLean, Catriona A. (external author)
  •   Garner, Brett
  •   Jenner, Andrew M. (external author)

Publication Date


  • 2016

Citation


  • Kreilaus, F., Spiro, A. S., McLean, C. A., Garner, B. & Jenner, A. M. (2016). Evidence for altered cholesterol metabolism in Huntington's disease post mortem brain tissue. Neuropathology and Applied Neurobiology, 42 535-546.

Scopus Eid


  • 2-s2.0-84951089389

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1629&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/607

Number Of Pages


  • 11

Start Page


  • 535

End Page


  • 546

Volume


  • 42