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

Abstract

The large pool of cholesterol in the brain is effi ciently isolated from other pools of cholesterol in the body by the effi cient blood-brain barrier (for reviews, see 1, 2 ). In contrast to the lipoprotein-bound cholesterol in the circulation, side-chain oxidized cholesterol metabolites are able to cross the blood-brain barrier and fl uxes of oxysterols have been demonstrated in both directions. We ( 3, 4 ) and others ( 5 ) have shown that about two-thirds of the synthesis of cholesterol in the brain is compensated for by a fl ow of 24S-hydroxycholesterol (24OHC) from the brain into the circulation. We also demonstrated a fl ux of the extracerebral metabolite 27-hydroxycholesterol (27OHC) from the circulation into the brain with a net uptake of this oxysterol ( 6 ). Most of the 27OHC present in the cerebrospinal fl uid originates from the circulation ( 7 ).Despite the substantial uptake of 27OHC by the brain, the levels of this oxysterol in the brain are very low, reaching only 5-10% of the levels of 24OHC ( 3,8 ). The reason for this is a highly effi cient metabolism. We have shown that the end metabolite of 27OHC in the brain is a steroid acid, 7 ␣ -hydroxy-3-oxo-4-cholestenoic acid, and that there is a continuous fl ux of this acid from the brain into the circulation ( 9 ). The nature of this acid as an end metabolite is illustrated by a very substantial accumulation of it in encapsulated brain hematomas ( 10 ). The rate-limiting step in the conversion of 27OHC into the steroid acid appears to be the introduction of a 7 ␣ -hydroxyl group catalyzed by the enzyme oxysterol 7 ␣ -hydroxylase, CYP7B1 ( 9 ). This enzyme is exclusively located in neuronal cells in the brain ( 11 ).Despite the fact that lipoprotein-bound cholesterol does not pass the blood-brain barrier ( 1, 2 ), hypercholesAbstract There is a signifi cant fl ux 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 signifi cantly 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 wh...

Cholestenoic acids regulate motor neuron survival via liver X receptors

“…Of these, 3β,7β-diHCA and the previously identified LXR ligand 3β-HCA were found to cause cell death, and the latter was present at high levels in patients with SPG5. Instead, 3β,7α-diHCA, which was found at low levels in ral tissue (46,47), 3β,7α-diHCA and 7α,26-diHCO have not been previously found in neural tissue or CSF. Importantly, the identification of these intermediates in the biosynthesis of 7αH,3O-CA lends further support to the hypothesis that 7αH,3O-CA is biosynthesized in the human brain (26).…”

“…Low levels of 26-HC have been found in human and mouse brain (Supplemental Results and Supplemental Table 4) and in human CSF, where it may be imported from the blood (25,(44)(45)(46). Conversely, 7αH,3O-CA, a metabolic product of 26-HC, is exported from brain to blood in humans (26).…”

27-Hydroxycholesterol mediates negative effects of dietary cholesterol on cognition in mice

“…High levels of circulating cholesterol are associated with high levels of 27OH and thus it is likely that hypercholesterolemia is associated with increased flux of 27OH into the brain. The brain of patients who had died with AD contained markedly increased levels of 27OH [8]. Under in vitro [9][10][11] as well as under some in vivo conditions [11], 27OH seems to accelerate neurodegenerative processes.…”

Brain Cholesterol Synthesis and Metabolism is Progressively Disturbed in the R6/1 Mouse Model of Huntington’s Disease: A Targeted GC-MS/MS Sterol Analysis

“…Although 27-OHC has been reported to be elevated in Alzheimer's disease (AD) brain tissue [31,32], the importance of this metabolic pathway has not been established in other neurodegenerative diseases, including HD.…”