Lovastatin fails to improve motor performance and survival in methyl-CpG-binding protein2-null mice

Abstract

Previous studies provided evidence for the alteration of brain cholesterol homeostasis in 129.Mecp2-null mice, an experimental model of Rett syndrome. The efficacy of statins in improving motor symptoms and prolonging survival of mutant mice suggested a potential role of statins in the therapy of Rett syndrome. In the present study, we show that Mecp2 deletion had no effect on brain and reduced serum cholesterol levels and lovastatin (1.5 mg/kg, twice weekly as in the previous study) had no effects on motor deficits and survival when Mecp2 deletion was expressed on a background strain (C57BL/6J; B6) differing from that used in the earlier study. These findings indicate that the effects of statins may be background specific and raise important issues to consider when contemplating clinical trials. The reduction of the brain cholesterol metabolite 24S-hydroxycholesterol (24S-OHC) found in B6.Mecp2-null mice suggests the occurrence of changes in brain cholesterol metabolism and the potential utility of using plasma levels of 24S-OHC as a biomarker of brain cholesterol homeostasis in RTT.DOI: http://dx.doi.org/10.7554/eLife.22409.001

Identification of Correlative Shifts in Indices of Brain Cholesterol Metabolism in the C57BL6/Mecp2tm1.1Bird Mouse, a Model for Rett Syndrome

“…Is it an adaptive response to the fall in the rate of cholesterol synthesis, or is there an event that causes the rate of conversion of cholesterol to 24 S ‐OHC to decrease through feedback inhibition, with the fall in cholesterol biosynthesis representing an adjustment for a slower rate of degradation? In addressing this question, it should be emphasized that although both the current studies and those of Villani et al () found a moderately suppressed concentration of 24 S ‐OHC in the brain of mature knockout mice, these are static measurements made in excised brains, unlike that for cholesterol synthesis, which was measured in vivo over a defined period of time. The data for the mRNA expression level of Cyp46A1 from three separate studies (Buchovecky et al, ; Lopez, Chuang, Posey, et al, ; Villani et al, ) are inconsistent and therefore cannot be used to substantiate the implication from the tissue 24 S ‐OHC content data that cholesterol degradation is slower in the brains of the mutant mice.…”

“…In addressing this question, it should be emphasized that although both the current studies and those of Villani et al () found a moderately suppressed concentration of 24 S ‐OHC in the brain of mature knockout mice, these are static measurements made in excised brains, unlike that for cholesterol synthesis, which was measured in vivo over a defined period of time. The data for the mRNA expression level of Cyp46A1 from three separate studies (Buchovecky et al, ; Lopez, Chuang, Posey, et al, ; Villani et al, ) are inconsistent and therefore cannot be used to substantiate the implication from the tissue 24 S ‐OHC content data that cholesterol degradation is slower in the brains of the mutant mice. Nevertheless, assuming that the 24 S ‐OHC content data do reflect a slower production rate, then the question arises as to what might happen to brain cholesterol synthesis rates if the production of 24 S ‐OHC was stimulated.…”

“…Thus, the main objective of the current study was to measure the absolute concentrations of 24 S ‐OHC, and also of various other classes of sterols, in the brains of MECP2 mutant mice at ~56 days of age. During the time that our analyses were being conducted, Villani et al () reported that brain 24 S ‐OHC concentrations were moderately but significantly lower in adult MECP2 mutant mice. This finding was made in the course of studies designed to re‐examine the effects of lovastatin on motor performance and survival in Mecp2‐null mice.…”

Statins and the Brain: More than Lipid Lowering Agents?

“…A similar conclusion was reached by Segatto and collaborators, who showed that the protein network of cholesterol homeostasis maintenance is severely altered on plasma and cultured skin fibroblasts of RTT patients [54], providing an additional finding that highlights that cholesterol metabolism may be taken into account as a new therapeutic option for the treatment of RTT. However, a recent study revealed that lovastatin had no effect on motor performance and survival when the deletion of the MeCP2 allele is expressed on a different background strain, suggesting that the response to lovastatin is under the control of inherent genetic or other biological mechanisms specific to the effects of lovastatin on brain function [158]. Thus, the effectiveness of lovastatin in RTT may be limited to those patients who reproduce alterations in cholesterol homeostasis similar to those described in mice responding to statins [50].…”

MeCP2 isoform e1 mutant mice recapitulate motor and metabolic phenotypes of Rett syndrome

“…Lipid metabolism was identified in an unbiased screen for rescue of RTT mouse phenotypes (30) and was later shown to result in metabolic alterations in RTT mice (31). Metabolic or oxidative stress alterations have been modified in several therapeutic trials of RTT mouse models (20), with some discrepancies by strain and age (32,33). Since the most promising therapeutics for RTT target metabolic pathways (34), such as AKT/mTOR (35,36), oxidative stress (28,37), and lipid metabolism (30,38), it is imperative to characterize developmental, metabolic, and motor phenotypes in female RTT mouse models.…”