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Cholesterol precursors and cholesterol levels are reduced in brain regions of Huntington's disease (HD) mice. Here we quantified the rate of in vivo de novo cholesterol biosynthesis in the HD brain. Samples from different brain regions and blood of the heterozygous knock-in mouse model carrying 175 CAG repeats (Q175) at different phenotypic stages were processed independently by two research units to quantify cholesterol synthesis rate by 2 H 2 O labeling and measure the concentrations of lathosterol, cholesterol and its brain-specific cholesterol catabolite 24-hydroxy-cholesterol (24OHC) by isotope dilution mass spectrometry. The daily synthesis rate of cholesterol and the corresponding concentration of lathosterol were significantly reduced in the striatum of heterozygous Q175 mice early in the disease course. We also report that the decrease in lathosterol was inversely correlated with CAG-size at symptomatic stage, as observed in striatal samples from an allelic series of HD mice. There was also a significant correlation between the fractional synthesis rates of total cholesterol and 24OHC in brain of wild-type (WT) and Q175 mice, supporting the evidence that plasma 24OHC may reflect cholesterol synthesis in the adult brain. This comprehensive analysis demonstrates consistent cholesterol biosynthesis defects in HD mouse models and suggests that plasma 24OHC may serve as a biomarker of brain cholesterol metabolism. [ABSTRACT FROM AUTHOR]

Dysfunctions in brain cholesterol homeostasis have been extensively related to brain disorders. The major elimination pathway of brain cholesterol is its hydroxylation into 24 ( S )-hydroxycholesterol by the cholesterol 24-hydroxylase (CYP46A1). Interestingly, there seems to be an association between CYP46A1 and high-order brain functions, in a sense that increased expression of this hydroxylase improves cognition, while a reduction leads to a poor cognitive performance. Moreover, increasing amount of epidemiological, biochemical and molecular evidence, suggests that CYP46A1 has a role in the pathogenesis or progression of neurodegenerative disorders, in which up-regulation of this enzyme is clearly beneficial. However, the mechanisms underlying these effects are poorly understood, which highlights the importance of studies that further explore the role of CYP46A1 in the central nervous system. In this review we summarize the major findings regarding CYP46A1, and highlight the several recently described pathways modulated by this enzyme from a physiological and pathological perspective, which might account for novel therapeutic strategies for neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Oxysterol binding protein (OSBP) is a cytosolic protein that undergoes ligand-induced binding to the Golgi apparatus and has been implicated in the regulation of cellular cholesterol metabolism. In the yeast Saccharomyces cerevisiae an OSBP homologue is involved in membrane trafficking through the Golgi complex. Prompted by the multitude of OSBP-related genes in the yeast genome, we carried out a search for human expressed sequence tags (ESTs) displaying homology to the sterol-binding domain of OSBP. This revealed a minimum of six novel OSBP-related proteins, designated ORP-1 to ORP-6. ORP cDNA probes were generated by reverse transcription-PCR from human liver mRNA, and used for Northern blot analysis of human tissue transcript panels. This verified that each of them represents a different gene product and showed that they display distinct tissue-specific expression patterns. The ORP-1 and -2 mRNA expression levels were similar to or higher than that of OSBP while the ORP-3 to -6 mRNAs were detected at lower levels in specific tissues. The most abundantly expressed new gene, ORP-1, was transcribed at strikingly high levels in the cortical areas of human brain and displayed sterol-regulated expression in a cultured human neuroblastoma cell line. This indicates that ORP-1 may play an important role in maintaining the sterol balance in cells of the central nervous system. Together with OSBP, the identified gene products constitute a novel human protein family that may provide a link between organellar sterol status and membrane dynamics.—Laitinen, S., V. M. Olkkonen, C. Ehnholm, and E. Ikonen. Family of human oxysterol binding protein (OSBP) homologues: a novel member implicated in brain sterol metabolism.

The cerebral synthesis of cholesterol is mainly handled by astrocytes, which are also responsible for apoproteins' synthesis and lipoproteins' assembly required for the cholesterol transport in the brain parenchyma. In Alzheimer disease (AD), these processes are impaired, likely because of the astrogliosis, a process characterized by morphological and functional changes in astrocytes. Several ATP-binding cassette transporters expressed by brain cells are involved in the formation of nascent discoidal lipoproteins, but the effect of beta-amyloid (Aβ) assemblies on this process is not fully understood. In this study, we investigated how of Aβ1-42-induced astrogliosis affects the metabolism of cholesterol in vitro. We detected an impairment in the cholesterol efflux of reactive astrocytes attributable to reduced levels of ABCA1 transporters that could explain the decreased lipoproteins' levels detected in AD patients. To approach this issue, we designed biomimetic HDLs and evaluated their performance as cholesterol acceptors. The results demonstrated the ability of apoA-I nanodiscs to cross the blood–brain barrier in vitro and to promote the cholesterol efflux from astrocytes, making them suitable as a potential supportive treatment for AD to compensate the depletion of cerebral HDLs. [ABSTRACT FROM AUTHOR]