Marked accumulation of 27-hydroxycholesterol in the brains of Alzheimer's patients with the Swedish APP 670/671 mutation

• Published in: Journal of lipid research Vol. 52; no. 5; pp. 1004 - 1010
• Main Authors: Shafaati, Marjan, Marutle, Amelia, Pettersson, Hanna, Lövgren-Sandblom, Anita, Olin, Maria, Pikuleva, Irina, Winblad, Bengt, Nordberg, Agneta, Björkhem, Ingemar
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2011; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Aged; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Protein Precursor - genetics; Blotting, Western; Brain - metabolism; Cholesterol - analogs & derivatives; Cholesterol - metabolism; cytochrome P450; Female; Humans; Hydroxycholesterols - metabolism; Male; Middle Aged; Mutation; oxysterols; Patient-Oriented and Epidemiological Research; phytosterols; Phytosterols - metabolism; Sitosterols - metabolism; phytosterols; cytochrome P450; oxysterols; Alzheimer's disease; cholesterol/metabolism
• ISSN: 0022-2275; 1539-7262; 1539-7262
• DOI: 10.1194/jlr.M014548

There is a significant flux of the neurotoxic oxysterol 27-hydroxycholesterol (27OHC) from the circulation across the blood-brain barrier. Because there is a correlation between 27OHC and cholesterol in the circulation and lipoprotein-bound cholesterol does not pass the blood-brain barrier, we have suggested that 27OHC may mediate the effects of hypercholesterolemia on the brain. We previously demonstrated a modest accumulation of 27OHC in brains of patients with sporadic Alzheimer's disease (AD), consistent with a role of 27OHC as a primary pathogenetic factor. We show here that there is a 4-fold accumulation of 27OHC in different regions of the cortexes of patients carrying the Swedish amyloid precursor protein (APPswe) 670/671 mutation. The brain levels of sitosterol and campesterol were not significantly different in the AD patients compared with the controls, suggesting that the blood-brain barrier was intact in the AD patients. We conclude that accumulation of 27OHC is likely to be secondary to neurodegeneration, possibly a result of reduced activity of CYP7B1, the neuronal enzyme responsible for metabolism of 27OHC. We discuss the possibility of a vicious circle in the brains of the patients with familial AD whereby neurodegenerative changes cause an accumulation of 27OHC that further accelerates neurodegeneration.