Identification of Correlative Shifts in Indices of Brain Cholesterol Metabolism in the C57BL6/Mecp2^tm1.1Bird Mouse, a Model for Rett Syndrome

Abstract

Rett syndrome (RS) is a pervasive neurodevelopmental disorder resulting from loss-of-function mutations in the X-linked gene methyl-Cpg-binding protein 2 (MECP2). Using a well-defined model for RS, the C57BL6/Mecp2 mouse, we have previously found a moderate but persistently lower rate of cholesterol synthesis, measured in vivo, in the brains of Mecp2 mice, starting from about the third week after birth. There was no genotypic difference in the total cholesterol concentration throughout the brain at any age. This raised the question of whether the lower rate of cholesterol synthesis in the mutants was balanced by a fall in the rate at which cholesterol was converted via cholesterol 24-hydroxylase (Cyp46A1) to 24S-hydroxycholesterol (24S-OHC), the principal route through which cholesterol is ordinarily removed from the brain. Here, we show that while there were no genotypic differences in the concentrations in plasma and liver of three cholesterol precursors (lanosterol, lathosterol, and desmosterol), two plant sterols (sitosterol and campesterol), and two oxysterols (27-hydroxycholesterol [27-OHC] and 24S-OHC), the brains of the Mecp2 mice had significantly lower concentrations of all three cholesterol precursors, campesterol, and both oxysterols, with the level of 24S-OHC being ~20% less than in their Mecp2 controls. Together, these data suggest that coordinated regulation of cholesterol synthesis and catabolism in the central nervous system is maintained in this model for RS. Furthermore, we speculate that the adaptive changes in these two pathways conceivably resulted from a shift in the permeability of the blood-brain barrier as implied by the significantly lower campesterol and 27-OHC concentrations in the brains of the Mecp2 mice.

Cholesterol Hydroxylating Cytochrome P450 46A1: From Mechanisms of Action to Clinical Applications

“…Similarly, cerebral cholesterol removal is also mainly enzymatic with the major route being 24-hydroxylation catalyzed by cytochrome P450 46A1 or CYP46A1 ( Bjorkhem et al, 1998 ; Lund et al, 2003 ). Studies in humans and mouse models detected changes in CYP46A1 expression or activity in a number of neurodegenerative diseases [Alzheimer’s (AD), Huntington’s (HD), Nieman-Pick type C, spinocerebellar ataxias (Sca), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS)] as well as other brain disorders (epilepsy, autism, Rett syndrome, glioblastoma, and prion infection) ( Figure 1 ; Loftus et al, 1997 ; Boussicault et al, 2016 ; Lopez et al, 2017 ; Grayaa et al, 2018 ; Lütjohann et al, 2018 ; Vejux et al, 2018 ; Han et al, 2019 ; Huang et al, 2019 ; Nobrega et al, 2019 ; Sodero, 2020 ; Steriade et al, 2020 ; Ali et al, 2021 ). Hence, CYP46A1 has emerged as a therapeutic target for these diseases because of its key role in cerebral cholesterol elimination.…”

Optimized Protocol for Subcutaneous Implantation of Encapsulated Cells Device and Evaluation of Biocompatibility

“…This technology represents an interesting alternative for treating chronic diseases requiring repeated injection of biologics, such as diabetes where the ECT is named GluSense (implantable glucose sensor; patent US2017/00720074A1). Clinical trials are currently ongoing to validate its potential applications for central nervous system (CNS) disorders (NCT01163825 1 ) and eye macular degeneration (NCT 01530659 and NCT03071965; see text footnote 1) ( Aebischer et al, 1996 ; Bachoud-Lévi et al, 2000 ; Bloch et al, 2004 ; Yizhar et al, 2011 ; Zhang et al, 2011 ; Eriksdotter-Jönhagen et al, 2012 ; Birch et al, 2013 , 2016 ; Lathuilière et al, 2015 ; Eyjolfsdottir et al, 2016 ; Lütjohann et al, 2018 ).…”

Sex disparate gut microbiome and metabolome perturbations precede disease progression in a mouse model of Rett syndrome

“…Blood and plasma metabolites from RTT patients have indicated that cholesterol metabolism, sphingolipid metabolism, and fatty acid metabolism are perturbed in RTT 49,[59][60][61][62][63] . Cholesterol and triglyceride metabolism has also been demonstrated to be dysregulated in the liver and brain in mouse models of RTT 38,50,[64][65][66] . Our data support a role for lipid dysregulation in RTT.…”

“…The striking patterns of increased fecal lipids, including SCFAs, in Mecp2-e1 -/+ females compared to controls across disease course indicate potential lipid malabsorption in the GI tract, which could impact the lipid composition of the brain. Furthermore, previous studies have found that lipid metabolism is disrupted in the brain of Mecp2 null mice 26, 49,50 . Thus, we tested the hypotheses that the lipidome was altered in the cortex from Mecp2-e1 mutants and correlated with the fecal metabolic changes.…”