27-Hydroxycholesterol contributes to disruptive effects on learning and memory by modulating cholesterol metabolism in the rat brain

Zhang, D.-D.; Yu, Huanling; Ma, Weiwei; Liu, Q.-R.; Han, Ji-Sheng; Wang, H.; Xiao, Rong

doi:10.1016/j.neuroscience.2015.05.022

Cited by 40 publications

(37 citation statements)

References 38 publications

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“…The absolute levels of not only 24S-OHC but other oxysterols such as 27-hydroxycholesterol should be determined along with the plasma and liver levels of these and related oxysterols. Inclusion of 27-hydroxycholesterol is warranted based on studies in other models suggesting that this oxysterol exerts regulatory effects on brain cholesterol homeostasis (Ali et al, 2013; Zhang et al, 2015). Be that as it may, these new data may help to explain why the brain cholesterol concentration in the mutant mice is unchanged from that seen in their matching wildtypes at all ages even though their rate of cholesterol synthesis falls below normal beginning in the third week after birth.…”

Section: Discussionmentioning

confidence: 99%

Suppression of brain cholesterol synthesis in male Mecp2-deficient mice is age dependent and not accompanied by a concurrent change in the rate of fatty acid synthesis

et al. 2017

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Mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2) are the principal cause of Rett syndrome, a progressive neurodevelopmental disorder afflicting 1 in 10,000 to 15,000 females. Studies using hemizygous Mecp2 mouse models have revealed disruptions to some aspects of their lipid metabolism including a partial suppression of cholesterol synthesis in the brains of mature Mecp2 mutants. The present studies investigated whether this suppression is evident from early neonatal life, or becomes manifest at a later stage of development. We measured the rate of cholesterol synthesis, in vivo, in the brains of male Mecp2−/y and their Mecp2+/y littermates at 7, 14, 21, 28, 42 and 56 days of age. Brain weight was consistently lower in the Mecp2−/y mice than in their Mecp2+/y controls except at 7 days of age. In the 7- and 14-day-old mice there was no genotypic difference in the rate of brain cholesterol synthesis but, from 21 days and later, it was always marginally lower in the Mecp2−/y mice than in age-matched Mecp2+/y littermates. At no age was a genotypic difference detected in either the rate of fatty acid synthesis or cholesterol concentration in the brain. Cholesterol synthesis rates in the liver and lungs of 56-day-old Mecp2−/y mice were normal. The onset of lower rates of brain cholesterol synthesis at about the time closure of the blood brain barrier purportedly occurs might signify a disruption to mechanism(s) that dictate intracellular levels of cholesterol metabolites including oxysterols known to exert a regulatory influence on the cholesterol biosynthetic pathway.

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Section: Discussionmentioning

confidence: 99%

Suppression of brain cholesterol synthesis in male Mecp2-deficient mice is age dependent and not accompanied by a concurrent change in the rate of fatty acid synthesis

et al. 2017

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“…Treatment of rodents with dietary cholesterol resulted in memory impairment characteristic of AD [15, 16], which we also have shown to be the case in the cholesterol-fed rabbit [17–21]. The inability of cholesterol to cross the blood-brain barrier and the fact that a high-cholesterol diet does not change cholesterol content in the rabbit brain [12, 17] suggest that serum cholesterol by itself does not increase AD risk.…”

Section: Introductionmentioning

confidence: 67%

“…It has been shown to act as a partial agonist of ERα in breast cancer cells [26, 29] and bone tissue [27, 58], but in the cardiovascular system, 27-OHC competitively antagonizes estrogen’s actions on ERα and ERβ [30] and promotes inflammation and atherosclerosis via ERα signaling [32]. Not much is known at present about the biological actions of 27-OHC in the brain although it has been shown that 27-OHC adversely affects cognition in rodents [15, 16]. Here we report that an increase in 27-OHC in the hippocampus is accompanied by changes in ER expression, a finding that could indicate a mechanistic link between oxysterols and neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

A High-Cholesterol Diet Increases 27-Hydroxycholesterol and Modifies Estrogen Receptor Expression and Neurodegeneration in Rabbit Hippocampus

Brooks

Dykes

Schreurs

2017

JAD

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Hypercholesterolemia has been implicated in numerous health problems from cardiovascular disease to neurodegeneration. High serum cholesterol levels in midlife have been associated with an increased risk of developing Alzheimer’s disease (AD) later in life which suggests that the pathways leading to AD pathology might be activated decades before the symptoms of the disease are detected. Cholesterol-fed animals, particularly cholesterol-fed rabbits, exhibit brain pathology similar to the changes found in brains of AD patients. Dietary cholesterol, which cannot pass the blood-brain barrier, is thought to influence central nervous system homeostasis by increased transport of its circulatory breakdown product, 27-hydroxycholesterol (27-OHC), into the brain. 27-OHC is an endogenous selective estrogen receptor modulator. Estrogen-mediated non-reproductive functions require estrogen receptors (ERs) and include modulation of mitochondrial function and structure, as well as regulation of synaptogenesis in the brain. ERs are located in brain areas affected early in AD pathogenesis, including the hippocampus. Here we report that increase in serum cholesterol, induced by feeding rabbits a high-cholesterol diet, is associated with higher levels of 27-OHC in the brain as well as increased levels of neurodegeneration in the hippocampus. Furthermore, these results are accompanied by changes in expression of ERs in the hippocampus as well as a decrease in hippocampal mitochondria. These findings provide an important insight into one of the possible mechanisms involved in the development of AD, and shed light on the processes that may antedate amyloid-β and tau phosphorylation changes currently hypothesized to cause AD symptomology and pathology.

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“…27-OHC may link high peripheral cholesterol with many CNS diseases through its ability to upregulate the brain renin-angiotensin system in an LXR-dependent manner [16]. Additionally, Zhang et al recently showed that peripheral injection of 27-OHC into rats upregulates LXRα and ATP-binding cassette transporter ABCA1 in the brain, downregulates HMG Co-A Reductase and LDLR, and produces dose-dependent impairments of spatial memory performance in the Morris Water Maze (MWM) task [17]. Heverin et al also report that Cyp27 deficient mice, which lack the enzyme necessary for 27-OHC production, do not experience the negative effects of high cholesterol diet on MWM performance and hippocampal Arc expression that their wild type littermates exhibit [18].…”

Section: Cholesterol Homeostasis In the Cnsmentioning

confidence: 99%

LXR Regulation of Brain Cholesterol: From Development to Disease

Courtney

Landreth

2016

Trends in Endocrinology & Metabolism

131

105

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Liver X Receptors (LXRs) are master regulators of cholesterol homeostasis and inflammation in the central nervous system (CNS). The brain, which contains a disproportionately large amount of the body's total cholesterol (~25%), requires a complex and delicately balanced cholesterol metabolism to maintain neuronal function. Dysregulation of cholesterol metabolism has been implicated in a number of neurodegenerative diseases including Alzheimer's (AD), Parkinson's (PD), and Huntington's (HD) diseases, among others. Due to their cholesterol sensing and anti-inflammatory activities, LXRs are positioned centrally in the everyday maintenance of central nervous system function. This review will focus on recent research into the role of LXRs in the CNS during normal development and homeostasis and in disease states.

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27-Hydroxycholesterol contributes to disruptive effects on learning and memory by modulating cholesterol metabolism in the rat brain

Cited by 40 publications

References 38 publications

Suppression of brain cholesterol synthesis in male Mecp2-deficient mice is age dependent and not accompanied by a concurrent change in the rate of fatty acid synthesis

Suppression of brain cholesterol synthesis in male Mecp2-deficient mice is age dependent and not accompanied by a concurrent change in the rate of fatty acid synthesis

A High-Cholesterol Diet Increases 27-Hydroxycholesterol and Modifies Estrogen Receptor Expression and Neurodegeneration in Rabbit Hippocampus

LXR Regulation of Brain Cholesterol: From Development to Disease

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