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

• Published in: Neuropathology and applied neurobiology 2016-10, Vol.42 (6), p.535-546
• Main Authors: Kreilaus, Fabian, Spiro, Adena S., McLean, Catriona A., Garner, Brett, Jenner, Andrew M.
• Format: Article
• Language: English
• Subjects: 24S-hydroxycholesterol; Aged; Aged, 80 and over; Autopsy; biomarker; Brain - metabolism; Cholesterol; Cholesterol - metabolism; DHCR24; Enzymes; Female; Homeostasis; Humans; Huntington Disease - metabolism; Huntingtons disease; lipid; Male; mass spectrometry; Metabolism; Metabolites; Middle Aged; oxysterol; Sterols
• ISSN: 0305-1846; 1365-2990
• DOI: 10.1111/nan.12286

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. Altered cholesterol homeostasis, decreased cholesterol metabolism and lipid oxidative stress suggest shared mechanisms between Huntington's disease and other neurodegenerative disorders and may provide common targets for therapeutic intervention.