Identification of Correlative Shifts in Indices of Brain Cholesterol Metabolism in the C57BL6/Mecp2tm1.1Bird Mouse, a Model for Rett Syndrome. Issue 4 (17th May 2018) - Lütjohann, Dieter
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 tm1.1Bird mouse, we have previously found a moderate but persistently lower rate of cholesterol synthesis, measured in vivo, in the brains of Mecp2 −/y 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 24 S ‐hydroxycholesterol (24 S ‐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 24 S ‐OHC), the brains of the Mecp2 −/y mice had significantly lower concentrations of all three cholesterol precursors, campesterol, and both oxysterols, with the level of 24 S ‐OHC being ~20% less than in their Mecp2 + / y 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 −/y mice.