24S-hydroxycholesterol in cerebrospinal fluid is elevated in early stages of dementia

Papassotiropoulos, Andreas; Lütjohann, Dieter; Bagli, Metin; Locatelli, S.; Jessen, Frank; Buschfort, R; Ptok, Ursula; Björkhem, Ingemar; Bergmann, Klaus von; Heun, Reinhard

doi:10.1016/s0022-3956(01)00050-4

Cited by 219 publications

(195 citation statements)

References 22 publications

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“…Plasma levels show a weak, if any, correlation with CSF levels. 55,56 24S-hydroxycholesterol was elevated in AD CSF, 56,57 but was only inconsistently increased in AD plasma. 56 -58 CSF and plasma 24S-hydroxycholesterol were reduced by statin and niacin treatment.…”

Section: S-hydroxycholesterolmentioning

confidence: 89%

Biomarkers of Alzheimer disease in plasma

Irizarry

2004

Neurotherapeutics

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Summary: Plasma and serum biochemical markers proposed for Alzheimer disease (AD) are based on pathophysiologic processes such as amyloid plaque formation [amyloid ␤-protein (A␤), A␤ autoantibodies, platelet amyloid precursor protein (APP) isoforms], inflammation (cytokines), oxidative stress (vitamin E, isoprostanes), lipid metabolism (apolipoprotein E, 24S-hydroxycholesterol), and vascular disease [homocysteine, lipoprotein (a)]. Most proteins or metabolites evaluated in plasma or serum thus far are, at best, biological correlates of AD: levels are statistically different in AD versus controls in some cohorts, but they lack sensitivity or specificity for diagnosis or for tracking response to therapy. Approaches combining panels of existing biomarkers or surveying the range of proteins in plasma (proteomics) show promise for discovering biomarker profiles that are characteristic of AD, yet distinct from nondemented patients or patients with other forms of dementia.

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Section: S-hydroxycholesterolmentioning

confidence: 89%

Biomarkers of Alzheimer disease in plasma

Irizarry

2004

Neurotherapeutics

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“…Despite numerous observations suggesting that ApoE4-associated deficits in sterol transport can result in neuronal dysfunction, there has not been direct evidence for abnormal sterol metabolism in the brain parenchyma of AD patients who express ApoE4, although several studies have used indirect measures to correlate brain cholesterol with ApoE polymorphisms. In one study, ApoE4 was associated with reduced levels of cholesterol, phospholipids, and fatty acids in the CSF of AD patients (Mulder et al 1998) and in a second study, 24S-hydroxycholesterol, a major cholesterol ester that is transported out of brain, was found to be elevated in the CSF and serum of AD patients with an apparent gene dosing effect of ApoE4 (Lutjohann et al 2000;Papassotiropoulos et al 2002). Although these findings suggest that ApoE4 perturbs cholesterol metabolism, it is not clear if more or less cholesterol is retained in the brain of AD patients expressing ApoE4.…”

Section: Introductionmentioning

confidence: 99%

ApoE4 disrupts sterol and sphingolipid metabolism in Alzheimer's but not normal brain

Bandaru

Troncoso

Wheeler

et al. 2009

Neurobiology of Aging

129

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The ε4 allele of ApoE is associated with an earlier onset and faster progression of Alzheimer's disease in patients with the familial form of this neurodegenerative condition. Although ApoE4 has been repeatedly associated with altered sphingomyelin and cholesterol levels in tissue culture and rodent models, there has not been a direct quantification of sphingomyelin or sterol levels in the brains of patients with different forms of ApoE. We measured the sphingolipid and sterol content of human brain tissues and found no evidence of perturbed sterol or sphingolipid biochemistry in the brains of individuals expressing ApoE4 who did not have a preexisting neurodegenerative condition. Nevertheless, ApoE4 was associated with gross abnormalities in the sterol and sphingolipid content of numerous brain regions in patients with Alzheimer's diseease. The findings suggest that ApoE4 may not by itself alter sterol or sphingolipid metabolism in the brain under normal conditions, but that other neuropathologic changes of Alzheimer's are required to unmask the effect of ApoE4, and to perturb sterol and sphingolipid biochemistry.

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“…2 mg/ml in plasma) (11,12), whereas the brain-derived oxysterol 24(S)-hydroxycholesterol (cholest-5-ene-3␤,24(S)-diol, C 5 -3␤,24(S)-diol) is present at a level of only about 1.5 ng/ml (cf. 40 -60 ng/ml in plasma) (supplemental Table S1) (11)(12)(13)(14). These values were determined by gas chromatography-mass spectrometry following hydrolysis of sterol fatty acid esters and derivatization, and thus represent the free plus fatty acid ester sterols as opposed to the levels of free unconjugated sterols, which are likely to be about an order of magnitude lower and are the likely bioactive forms.…”

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confidence: 99%

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

Ogundare

Theofilopoulos

Lockhart

et al. 2010

Journal of Biological Chemistry

111

123

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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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24S-hydroxycholesterol in cerebrospinal fluid is elevated in early stages of dementia

Cited by 219 publications

References 22 publications

Biomarkers of Alzheimer disease in plasma

Biomarkers of Alzheimer disease in plasma

ApoE4 disrupts sterol and sphingolipid metabolism in Alzheimer's but not normal brain

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

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