Brain Cholesterol Metabolism, Oxysterols, and Dementia

Abstract

Cholesterol metabolism is implicated in the etiology of Alzheimer’s disease (AD) and amyloid production in the brain. While brain cholesterol cannot be measured directly in vivo, the oxysterol, 24S-hydroxycholesterol (24-OHC), is the predominant metabolite of brain cholesterol and can be measured in the blood. The aim of this review is to evaluate plasma 24-OHC as a potential biomarker of AD risk and discuss factors related to its levels in the brain and blood. This systematic review examines studies published between 1950 and June 2012 that examined the relationship between plasma 24-OHC, cognition, brain structure, and dementia using the following key words (“24S-hydroxycholesterol” or “24-hydroxycholesterol”) and (“Brain” or “Cognitive”). We found a total of 28 studies of plasma 24-OHC and neurodegenerative disease, including a subset of 12 that used dementia as a clinical endpoint. These studies vary in the direction of the observed associations. Results suggest plasma 24-OHC may be higher in the early stages of cognitive impairment and lower in more advanced stages of AD when compared to cognitively normal controls. Measures of 24-OHC in the blood may be an important potential marker for cholesterol metabolism in the brain and risk of AD. Further studies of plasma 24-OHC and dementia must account for the stage of disease, establish the temporal trends in oxysterol concentrations, and employ neuroimaging modalities to assess the structural and metabolic changes occurring in the brain prior to the onset of cognitive impairment.

Plasma Signature of Neurological Disease in the Monogenetic Disorder Niemann-Pick Type C

“…Plasma oxysterols (7-ketocholetserol and 3␤,5␣,6␤-triol) generated by non-enzymatic pathways are largely produced by the liver (43,44) and thus are likely to be more useful to understand liver pathology rather than brain pathology. However, 24(S)-HC is derived from cholesterol by an enzyme, 24-hydroxylase, which is primarily expressed in the neurons of the central nervous system (45,46). As shown in Fig.…”

High Cholesterol Diet Increases Expression of Cholesterol 24-Hydroxylase and BACE1 in Rat Hippocampi: Implications for the Effect of Diet Cholesterol on Memory

“…Both oxysterols are potent modulators of cholesterol synthesis and ligands for liver X receptor (LXR) a and b, members of the nuclear receptor family of transcription factors, which play an important role in lipid homeostasis in the central nervous system. In the current study, we tried to find out whether hypercholesterolemia can affect the expression of CYP46A1in the hippocampi of rats and we observed a clear increase in its expression, indicative of disturbed cholesterol homeostasis in the hippocampus (10).…”

“…However, this does not mean that there is no link between these two features of cholesterol metabolism. Many in vitro and in vivo studies (10)(11)(12), investigating the mechanism by which hypercholesterolemia on the brain leads to AD pathology, have revealed that plasma and the brain exchange a number of oxysterols such as 24 OHC), the major brain cholesterol metabolite, and 27(S)-hydroxycholesterol, one of the plasma cholesterol metabolites that cross the BBB in equal amounts. The enzyme responsible for the production of 24S-OHC is CYP46A1, which belongs to the cytochrome P450 super family, almost exclusively expressed in neuronal cells.…”

Esterification of 24S-OHC induces formation of atypical lipid droplet-like structures, leading to neuronal cell death

“…We propose that DART-MS analysis may serve as a useful tool for investigation not just of 24S-OHC esters, as in our present study, but of a wide variety of esters of sterols and fatty acids. For example, there has been growing interest in oxysterol research because there are a number of bioactivities of oxysterols that have received much attention (40,41), and oxysterols also have potential for use as biomarkers of neurodegenerative diseases (10,42,43). Although it will be necessary to devise appropriate techniques before DART-MS can be used for precise quantitative analysis, it is thought that the DART-MS method will ultimately be valuable for evaluation not only of free oxysterol, but also of oxysterol esters in the tissue, plasma, and cerebrospinal fluid of patients suffering from neurodegenerative disease.…”