Abstract
Using liquid chromatography – mass spectrometry in combination with derivatisation chemistry we profiled the oxysterol and cholestenoic acid content of cerebrospinal fluid from patients with Alzheimer's disease (n = 21), vascular dementia (n = 11), other neurodegenerative diseases (n = 15, Lewy bodies dementia, n = 3, Frontotemporal dementia, n = 11) and controls (n = 15). Thirty different sterols were quantified and the bile acid precursor 7α,25-dihydroxy-3-oxocholest-4-en-26-oic acid found to be reduced in abundance in cerebrospinal fluid of Alzheimer's disease patient-group. This was the only sterol found to be changed amongst the different groups.
Highlights
Cholesterol has been linked to the aetiology of Alzheimer's disease (AD) for decades with the ε4 allele of apolipoprotein E gene (APOE) being the most robust genetic risk factor for sporadic AD [1,2]
Björkhem and colleagues have suggested the balance between 24S-hydroxycholesterol and its positional isomer (25 R)26-hydroxycholesterol in brain may affect the production of beta-amyloid in brain [14]. (25R)26Hydroxycholesterol may be formed via CYP27A1 mediated oxidation of cholesterol in brain or imported into brain from extracerebral sources [14,15,16]. (25R) 26-Hydroxycholesterol is elevated in AD brain [17] and Björkhem et al have suggested (25R)26-hydroxycholesterol may provide a missing link between hypercholesterolemia and AD [14]
This selection has previously been validated by Crick et at for some C27 acids [37] and here for 7α,25-dihydroxy-3-oxocholest-4-en-26-oic acid using the standard additions method where a plot of measured concentration against theoretical concentration gave a straight line with R2 > 0.994
Summary
Cholesterol has been linked to the aetiology of Alzheimer's disease (AD) for decades with the ε4 allele of apolipoprotein E gene (APOE) being the most robust genetic risk factor for sporadic AD [1,2]. In brain the dominant oxysterol is 24S-hydroxycholesterol [10], formed in neurons by oxidation of cholesterol by CYP46A1 (cytochrome P450 family 46 subfamily A member 1) [11], this can be metabolised further in CNS [12] or exported as the intact molecule over the BBB [13]. (25R)26Hydroxycholesterol may be formed via CYP27A1 (cytochrome P450 family 27 subfamily A member 1) mediated oxidation of cholesterol in brain or imported into brain from extracerebral sources [14,15,16]. Björkhem and colleagues have suggested the balance between 24S-hydroxycholesterol and its positional isomer (25 R)26-hydroxycholesterol (common name 27-hydroxycholesterol) in brain may affect the production of beta-amyloid in brain [14]. (25R)26Hydroxycholesterol may be formed via CYP27A1 (cytochrome P450 family 27 subfamily A member 1) mediated oxidation of cholesterol in brain or imported into brain from extracerebral sources [14,15,16]. (25R) 26-Hydroxycholesterol is elevated in AD brain [17] and Björkhem et al have suggested (25R)26-hydroxycholesterol may provide a missing link between hypercholesterolemia and AD [14]
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