27-Hydroxycholesterol mediates negative effects of dietary cholesterol on cognition in mice

Heverin, Maura; Maioli, Silvia; Pham, T. M.; Mateos, Laura; Camporesi, Elena; Ali, Zeina; Winblad, Bengt; Cedazo-Mı́nguez, Ángel; Björkhem, Ingemar

doi:10.1016/j.bbr.2014.10.018

Cited by 54 publications

(56 citation statements)

References 24 publications

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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: 65%

“…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. This assumption was validated in a study that reported memory impairment in cholesterol-fed mice but not in cholesterol-fed mutant mice lacking the enzyme CYP27A1 that metabolizes cholesterol into 27-OHC [16]. This study suggested that 27-OHC mediated the negative effects of cholesterol on memory.…”

Section: Introductionmentioning

confidence: 66%

“…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%

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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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Section: Introductionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…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]. Interestingly, 27-OHC may also play a complicated role in AD pathology, as 27-OHC treatments have been observed to upregulate amyloid beta (Aβ) production in neuronal cell lines [19,20] but downregulate Aβ production, potentially in an LXR-mediated manner, in primary human neurons [21].…”

Section: Cholesterol Homeostasis In the Cnsmentioning

confidence: 99%

LXR Regulation of Brain Cholesterol: From Development to Disease

Courtney

Landreth

2016

Trends in Endocrinology & Metabolism

135

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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“…CSF 27HC concentration is correlated with soluble amyloid precursor protein (sAPP) [95]. Furthermore, cholesterol-mediated memory impairment is ablated in CYP27A1 −/− mice, while 27HC treatment results spatial learning and memory impairment, indicating 27HC mediates at least some aspects of cholesterol-induced AD progression [96, 97]. …”

Section: 27hc Is Associated With Cognitive Impairmentmentioning

confidence: 99%

27-Hydroxycholesterol, an endogenous selective estrogen receptor modulator

Nelson

2017

Maturitas

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Estrogen receptors (ERs) mediate the actions of the steroidal estrogens, and are important for the regulation of several physiological and pathophysiological processes, including reproduction, bone physiology, cardiovascular physiology and breast cancer. The unique pharmacology of the ERs allows for certain ligands, such as tamoxifen, to elicit tissue- and context-specific responses, ligands now referred to as selective estrogen receptor modulators (SERMs). Recently, the cholesterol metabolite 27-hydroxychoelsterol (27HC) has been defined as an endogenous SERM, with activities in atherosclerosis, osteoporosis, breast and prostate cancers, and neural degenerative diseases. Since 27HC concentrations closely mirror those of cholesterol, it is possible that 27HC mediates many of the biological effects of cholesterol. This paper provides an overview of ER pharmacology and summarizes the work to date implicating 27HC in various diseases. Wherever possible, we highlight clinical data in support of a role for 27HC in the diseases discussed.

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27-Hydroxycholesterol mediates negative effects of dietary cholesterol on cognition in mice

Cited by 54 publications

References 24 publications

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

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

27-Hydroxycholesterol, an endogenous selective estrogen receptor modulator

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