title: Marked accumulation of 27-hydroxycholesterol in the brains of Alzheimer's patients with the Swedish APP 670/671 mutation.
abstract: 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.
authors.affiliation: Department of Laboratory Medicine Care Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
authors.forename: Marjan
authors.initials: M
authors.lastname: Shafaati
authors.forename: Amelia
authors.initials: A
authors.lastname: Marutle
authors.forename: Hanna
authors.initials: H
authors.lastname: Pettersson
authors.forename: Anita
authors.initials: A
authors.lastname: Lövgren-Sandblom
authors.forename: Maria
authors.initials: M
authors.lastname: Olin
authors.forename: Irina
authors.initials: I
authors.lastname: Pikuleva
authors.forename: Bengt
authors.initials: B
authors.lastname: Winblad
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordberg
authors.forename: Ingemar
authors.initials: I
authors.lastname: Björkhem
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002784:Cholesterol / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010840:Phytosterols / Q000378:metabolism; D012855:Sitosterols / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D006888:Hydroxycholesterols; D010840:Phytosterols; D012855:Sitosterols; C021273:campesterol; C025473:gamma-sitosterol; C076996:27-hydroxycholesterol; D002784:Cholesterol