Sex difference in flux of 27‐hydroxycholesterol into the brain

Abstract

Background and Purpose: The cerebrospinal fluid (CSF)/plasma albumin ratio (QAlb) is believed to reflect the integrity of the blood-brain barrier (BBB). Recently, we reported that QAlb is lower in females. This may be important for uptake of neurotoxic 27-hydroxycholesterol (27OH) by the brain in particular because plasma levels of 27OH are higher in males. We studied sex differences in the relation between CSF and plasma levels of 27OH and its major metabolite 7α-hydroxy-3-oxo-4-cholestenoic acid (7HOCA) with QAlb. We tested the possibility of sex differences in the brain metabolism of 27OH and if its flux into the brain disrupted integrity of the BBB.Experimental Approach: We have examined our earlier studies looking for sex differences in CSF levels of oxysterols and their relation to QAlb. We utilized an in vitro model for the BBB with primary cultured brain endothelial cells to test if 27OH has a disruptive effect on this barrier. We measured mRNA and protein levels of CYP7B1 in autopsy brain samples.

The Interaction Effect of 27‐Hydroxycholesterol Metabolism Disorder and CYP27A1 Single Nucleotide Polymorphisms in Mild Cognitive Impairment: Evidence from a Case–Control Study

“…[23] Similarly, a previous study in Sweden in-vestigated the sex differences in 27-OHC metabolism, the results showed that the flux of 27-OHC into the brain is higher in males compared with females. [24] The level of 27-OHC was positively associated with TC, LDL-C, and Non-HDL-C in current study, suggesting that cholesterol metabolism was related to 27-OHC. A community-based cohort study in French recruited nondemented subjects among 65 years and over demonstrated that high TC was correlated to an increase of cognitive decline in men instead of women.…”

AT1 receptor autoantibodies mediate effects of metabolic syndrome on dopaminergic vulnerability

“…It has been suggested that the deleterious effects of hypercholesterolemia on cognitive dysfunction and neurodegeneration may be mediated by increased flux of 27OH cholesterol across the BBB (Bjorkhem et al, 2009;Loera-Valencia et al, 2019). However, recent studies concluded that circulating 27OH cholesterol does not have a direct effect on BBB permeability, and that an unknown circulatory factor with a level correlated to level of 27OH cholesterol may increase BBB permeability (Parrado-Fernandez et al, 2021). The present study suggests that circulating AT1-AA may be this unknown factor increasing permeability of BBB, as strong correlation between AT1-AA and 27OH cholesterol was observed in our model.…”

Connecting the Dots Between Hypercholesterolemia and Alzheimer’s Disease: A Potential Mechanism Based on 27-Hydroxycholesterol

“…A previous study suggests that approximately 5 mg of 27-OHC per day flows into the brain and that more 27-OHC will enter the brain if the integrity and function of the BBB is impaired ( Heverin et al, 2005 ; Björkhem et al, 2009 ). Generally, the flux of 27-OHC into the brain is higher in males than females, but oxygen steroid levels are not affected by sex differences ( Parrado-Fernandez et al, 2021 ). In neuronal cells, 27-OHC will be metabolized to 7a-hydroxy-3-oxo-4-cholestenoic acid (7-HOCA) by the action of the CYP7B1 enzyme ( Meaney et al, 2007 ).…”