Is it possible to improve memory function by upregulation of the cholesterol 24S-hydroxylase (CYP46A1) in the brain?

We previously described a heterozygous mouse model overexpressing human HA-tagged 24S-hydroxylase (CYP46A1) utilizing a ubiquitous expression vector. In this study, we generated homozygotes of these mice with circulating levels of 24OH 30-60% higher than the heterozygotes. Female homozygous CYP46A1 transgenic mice, aged 15 months, showed an improvement in spatial memory in the Morris water maze test as compared to the wild type mice.

On the regulatory role of side-chain hydroxylated oxysterols in the brain. Lessons from CYP27A1 transgenic and Cyp27a1(-/-) mice.

The two oxysterols, 27-hydroxycholesterol (27OH) and 24S-hydroxycholesterol (24OH), are both inhibitors of cholesterol synthesis and activators of the liver X receptor (LXR) in vitro. Their role as physiological regulators under in vivo conditions is controversial, however. In the present work, we utilized a previously described mouse model with overexpressed human sterol 27-hydroxylase (CYP27A1).

Marked accumulation of 27-hydroxycholesterol in the brains of Alzheimer's patients with the Swedish APP 670/671 mutation.

There is a significant flux of the neurotoxic oxysterol 27-hydroxycholesterol (27OHC) from the circulation across the blood-brain barrier. Because there is a correlation between 27OHC and cholesterol in the circulation and lipoprotein-bound cholesterol does not pass the blood-brain barrier, we have suggested that 27OHC may mediate the effects of hypercholesterolemia on the brain. We previously demonstrated a modest accumulation of 27OHC in brains of patients with sporadic Alzheimer's disease (AD), consistent with a role of 27OHC as a primary pathogenetic factor.

On the mechanism of accumulation of cholestanol in the brain of mice with a disruption of sterol 27-hydroxylase.

The rare disease cerebrotendinous xanthomatosis (CTX) is due to a lack of sterol 27-hydroxylase (CYP27A1) and is characterized by cholestanol-containing xanthomas in brain and tendons. Mice with the same defect do not develop xanthomas. The driving force in the development of the xanthomas is likely to be conversion of a bile acid precursor into cholestanol.

Marked variability in hepatic expression of cytochromes CYP7A1 and CYP27A1 as compared to cerebral CYP46A1. Lessons from a dietary study with omega 3 fatty acids in hamsters.

Two diets simulating the recommendations of the American Heart Association to increase the intake of n-3 polyunsaturated fatty acids (n-3 PUFAs) were tested on Golden Syrian hamsters and compared to the diet simulating the current estimated consumption of fat in the United States. N-3 PUFAs were evaluated for their effects on serum and brain lipids and on the three cytochrome P450 enzymes (CYPs 7A1, 27A1, and 46A1) that play key roles in cholesterol elimination from different organs. Hamsters on the highest concentration of n-3 PUFAs had a statistically significant decrease in LDL and HDL cholesterol and no change in serum total cholesterol and triglycerides levels.

The antifungal drug voriconazole is an efficient inhibitor of brain cholesterol 24S-hydroxylase in vitro and in vivo.

Cholesterol 24S-hydroxylase (CYP46A1) is of key importance for cholesterol homeostasis in the brain. This enzyme seems to be resistant toward most regulatory factors and at present no drug effects on its activity have been described. The crystal structures of the substrate-free and substrate-bound CYP46A1 were recently determined (Mast et al.

Transcriptional regulation of cholesterol 24-hydroxylase by histone deacetylase inhibitors.

The mechanistic basis for the tissue specific expression of cholesterol elimination pathways is poorly understood. To gain additional insight into this phenomenon we considered it of interest to investigate if epigenetic mechanisms are involved in the regulation of the brain-specific enzyme cholesterol 24-hydroxylase (CYP46A1), a key regulator of brain cholesterol elimination. We demonstrated a marked time-dependent derepression of the expression of CYP46A1, in response to treatment with the potent histone deacetylase (HDAC) inhibitor Trichostatin A.

Levels of ApoE in cerebrospinal fluid are correlated with Tau and 24S-hydroxycholesterol in patients with cognitive disorders.

Evidence was recently presented from in vitro studies that 24S-hydroxycholesterol acts as a signalling molecule inducing apoE-mediated cholesterol efflux from astrocytoma cells, and that there is a direct effect of the oxysterol on apoE transcription, protein synthesis and secretion. Consistent with this mechanism, a significant correlation is demonstrated here between levels of apoE and 24S-hydroxycholesterol in cerebrospinal fluid from patients with Alzheimer's disease and patients with mild cognitive impairment. Such a correlation was not found in control patients.

Studies on the cholesterol-free mouse: strong activation of LXR-regulated hepatic genes when replacing cholesterol with desmosterol.

Objective: Characterization of cholesterol homeostasis in male mice with a genetic inactivation of 3beta-hydroxysteroid-delta24-reductase, causing replacement of almost all cholesterol with desmosterol.

Methods And Results: There was an increase in hepatic sterol synthesis and markedly increased fecal loss of neutral sterols. Fecal excretion of bile acids was similar in knockout mice and in controls.

Are the CSF levels of 24S-hydroxycholesterol a sensitive biomarker for mild cognitive impairment?

There is a need for effective biomarkers showing whether or not a patient with mild cognitive impairment (MCI) will progress to Alzheimer's disease (AD) with dementia. At the present three cerebrospinal fluid (CSF) biomarkers are in general use: total tau, phospho-tau and beta-Amyloid. These markers are regarded to have high capacity to differentiate early AD from normal ageing.