Abstract
Cytochrome P450 46A1 (CYP46A1) is a brain-specific cholesterol 24-hydroxylase responsible for the majority of cholesterol elimination from the brain. Genetically increased CYP46A1 expression in mice leads to improved cognition and decreases manifestations of Alzheimer disease. We found that four pharmaceuticals (efavirenz (EFV), acetaminophen, mirtazapine, and galantamine) prescribed for indications unrelated to cholesterol maintenance increased CYP46A1 activity in vitro. We then evaluated the anti-HIV medication EFV for the mode of interaction with CYP46A1 and the effect on mice. We propose a model for CYP46A1 activation by EFV and show that EFV enhanced CYP46A1 activity and cerebral cholesterol turnover in animals with no effect on the levels of brain cholesterol. The doses of EFV administered to mice and required for the stimulation of their cerebral cholesterol turnover are a hundred times lower than those prescribed to HIV patients. At such small doses, EFV may be devoid of adverse effects elicited by high drug concentrations. CYP46A1 could be a novel therapeutic target and a tool to further investigate the physiological and medical significance of cerebral cholesterol turnover.
Highlights
Elevation of cerebral cholesterol turnover in mice due to increased Cytochrome P450 46A1 (CYP46A1) expression has palliative effects on hallmarks of Alzheimer disease
We propose a model for CYP46A1 activation by EFV and show that EFV enhanced CYP46A1 activity and cerebral cholesterol turnover in animals with no effect on the levels of brain cholesterol
In the screening assay with purified CYP46A1, the seven selected pharmaceuticals activated the enzyme to different degrees: very weakly, weakly, or moderately
Summary
Elevation of cerebral cholesterol turnover in mice due to increased CYP46A1 expression has palliative effects on hallmarks of Alzheimer disease. Animal data suggest that increasing Cyp46a1 levels or enzyme activity could be beneficial for humans of older age, leading to cognitive enhancements in healthy individuals and slowing the disease progression in patients with Alzheimer disease. Predominant expression in the brain [13] makes CYP46A1 attractive as a new therapeutic target and a tool for studies of cerebral cholesterol homeostasis. This laboratory is investigating the potential of existing medications to stimulate CYP46A1 activity in the brain. We demonstrate that the anti-HIV medication efavirenz (EFV) stimulates CYP46A1 in vitro and in vivo, leading to an increase in cholesterol turnover in mouse brain. Our findings have direct medical relevance and could immediately be tested on elderly humans for enhancement of cognition and effect on progression of Alzheimer disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
