Crossing the barrier: net flux of 27-hydroxycholesterol into the human brain

Heverin, Maura; Meaney, Steve; Lütjohann, Dieter; Diczfalusy, Ulf; Wahren, John; Björkhem, Ingemar

doi:10.1194/jlr.m500024-jlr200

Cited by 231 publications

(252 citation statements)

References 27 publications

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“…One possibility is that cholesterol metabolites that can cross the blood brain barrier, particularly 27-hydroxcholesterol, may have had some influence on learning (Heverin et al, 2005). There is some evidence, albeit indirect, for the involvement of 27-hydroxycholesterol in learning and memory because levels of this oxysterol are significantly reduced in patients with mild cognitive impairment, Alzheimer's disease and vascular dementia (Kolsch et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Cholesterol enhances classical conditioning of the rabbit heart rate response

Schreurs

Smith-Bell

Darwish

et al. 2007

Behavioural Brain Research

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The cholesterol-fed rabbit is a model of atherosclerosis and has been proposed as an animal model of Alzheimer's disease. Feeding rabbits cholesterol has been shown to increase the number of beta amyloid immunoreactive neurons in the cortex. Addition of copper to the drinking water of cholesterol-fed rabbits can increase this number still further and may lead to plaque-like structures. Classical conditioning of the nictitating membrane response in cholesterol-fed rabbits is retarded in the presence of these plaque-like structures but may be facilitated in their absence. In a factorial design, rabbits fed 2% cholesterol or a normal diet (0% cholesterol) for 8 weeks with or without copper added to the drinking water were given trace classical conditioning using a tone and periorbital electrodermal stimulation to study the effects of cholesterol and copper on classical conditioning of heart rate and the nictitating membrane response. Cholesterol-fed rabbits showed significant facilitation of heart rate conditioning and conditioning-specific modification of heart rate relative to normal diet controls. Consistent with previous research, cholesterol had minimal effects on classical conditioning of the nictitating membrane response when periorbital electrodermal stimulation was used as the unconditioned stimulus. Immunohistochemical analysis showed a significant increase in the number of beta amyloid positive neurons in the cortex, hippocampus and amygdala of the cholesterol-fed rabbits. Supplementation of drinking water with copper increased the number of beta amyloid positive neurons in the cortex of cholesterol-fed rabbits but did not produce plaque-like structures or have a significant effect on heart rate conditioning. The data provide additional support for our finding that, in the absence of plaques, dietary cholesterol may facilitate learning and memory. Cholesterol enhances rabbit heart rate conditioningThe cholesterol-fed rabbit has been used as an animal model of atherosclerosis since 1913 when Anitchkow first demonstrated that a cholesterol diet induced vascular lesions (Bocan, 1998;Fan & Watanabe, 2000;Finking & Hanke, 1997;Moghadasian, 2002). More recently, the cholesterol-fed rabbit has been proposed as an animal model of Alzheimer's disease (Ghribi, Larsen, Schrag, & Herman, 2006;Sjogren, Mielke, Gustafson, Zandi, & Skoog, 2006 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Sparks, 1997;Sparks, Martin, Gross, & Hunsaker III, 2000;Zatta, Zambenedetti, Stella, & Licastro, 2002). Based on the observation that patients with heart disease had beta amyloid st...

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Section: Discussionmentioning

confidence: 99%

Cholesterol enhances classical conditioning of the rabbit heart rate response

Schreurs

Smith-Bell

Darwish

et al. 2007

Behavioural Brain Research

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“…However, normal levels of this oxysterol are relatively very low in the hippocampus in comparison to 24S--OHC. We have previously shown that a substantial part of this cerebral 27--OHC originates from outside the brain ( Heverin et al, 2005). While we have evidence to suggest that it further metabolized to an acid which then fluxes out of the brain we do not know the function of 27--OHC in the brain ( Meaney et al, 2007).…”

Section: Introductionmentioning

confidence: 86%

Bi-lateral changes to hippocampal cholesterol levels during epileptogenesis and in chronic epilepsy following focal-onset status epilepticus in mice

Heverin

Engel

Meaney³

et al. 2012

Brain Research

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Brain cholesterol homeostasis has been shown to be disrupted in neurodegenerative conditions such as Alzheimer's and Huntington's diseases. Investigations in animal models of seizure--induced brain injury suggest that brain cholesterol levels are altered by prolonged seizures (status epilepticus) and are a feature of the pathophysiology of temporal lobe epilepsy. The present study measured hippocampal sterol levels in a model of unilateral hippocampal injury triggered by focal--onset status epilepticus, and in chronically epileptic mice. Status epilepticus was induced by intra--amygdala microinjection of kainic acid and ipsilateral and contralateral hippocampus analyzed. No significant changes were found for ipsilateral or contralateral hippocampal levels of desmosterol or lathosterol at any time after SE as measured by gas chromatographymass spectrometry. 24S--hydroxycholesterol and cholesterol levels were unchanged up to 24 h after status epilepticus but were decreased in the ipsilateral hippocampus during early epileptogenesis and in chronically epileptic mice. Levels of cholesterol were also reduced in the contralateral hippocampus during epileptogenesis and in chronic epileptic mice. Treatment of mice with the anti--inflammatory cholesterol synthesis inhibitor lovastatin did not alter seizures during status epilepticus or seizure--induced neuronal death. Thus, changes to hippocampal cholesterol homeostasis predominantly begin during epileptogenesis, occur bi--laterally even when the initial precipitating injury is unilateral, and continue into the chronic epileptic period.

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“…The data indicate that LXR ligands are efficiently deactivated in brain before passage into CSF. This is true whether the ligands are supplied via the bloodstream (21) or produced in brain (22,24).…”

Section: Discussionmentioning

confidence: 99%

“…The levels of 7␣-hydroxy-3-oxocholest-4-en-26-oic and 3␤-hydroxycholest-5-en-26-oic acid in CSF were found to be 7.170 Ϯ 2.826 and 0.416 Ϯ 0.193 ng/ml, respectively. These C 27 bile acids could originate in plasma and be transferred to CSF or alternatively be formed in brain from 27-hydroxycholesterol (22,24), which is itself suggested to be imported into brain from plasma (21). The possibility also exists that C 27 bile acids could be formed in brain from cholesterol itself.…”

Section: Identification Of Sterols and Bile Acids In Csfmentioning

confidence: 99%

“…24(S)-Hydroxycholesterol is a net export product from the central nervous system (18) and is ultimately transported to the liver where it is metabolized into bile acids (19,20). On the other hand, 27-hydroxycholesterol (cholest-5-ene-3␤,26-diol, C 5 -3␤,26-diol) is a net import product to the central nervous system (21), and recent data suggest that it is metabolized in brain to 7␣-hydroxy-3-oxocholest-4-en-26-oic acid (CA 4 -7␣-ol-3-one) (22). This acid is an intermediate in the acidic bile acid biosynthetic pathway (19) and can be formed extrahepatically (23), and its formation in brain arouses interest in other bile acid precursors and bile acids formed in brain.…”

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confidence: 99%

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Cerebrospinal Fluid Steroidomics: Are Bioactive Bile Acids Present in Brain?

Ogundare

Theofilopoulos

Lockhart

et al. 2010

Journal of Biological Chemistry

114

124

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In this study we have profiled the free sterol content of cerebrospinal fluid by a combination of charge tagging and liquid chromatography-tandem mass spectrometry. Surprisingly, the most abundant cholesterol metabolites were found to be C 27 and C 24 intermediates of the bile acid biosynthetic pathways with structures corresponding to 7␣-hydroxy-3-oxocholest-4-en-26-oic acid (7.170 ؎ 2.826 ng/ml, mean ؎ S.D., six subjects), 3␤-hydroxycholest-5-en-26-oic acid (

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Crossing the barrier: net flux of 27-hydroxycholesterol into the human brain

Cited by 231 publications

References 27 publications

Cholesterol enhances classical conditioning of the rabbit heart rate response

Cholesterol enhances classical conditioning of the rabbit heart rate response

Bi-lateral changes to hippocampal cholesterol levels during epileptogenesis and in chronic epilepsy following focal-onset status epilepticus in mice

Cerebrospinal Fluid Steroidomics: Are Bioactive Bile Acids Present in Brain?

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