Assessment of cholesterol homeostasis in the living human brain

Abstract

Alterations in brain cholesterol homeostasis have been broadly implicated in neurological disorders. Notwithstanding the complexity by which cholesterol biology is governed in the mammalian brain, excess neuronal cholesterol is primarily eliminated by metabolic clearance via cytochrome P450 46A1 (CYP46A1). No methods are currently available for visualizing cholesterol metabolism in the living human brain; therefore, a noninvasive technology that quantitatively measures the extent of brain cholesterol metabolism via CYP46A1 could broadly affect disease diagnosis and treatment options using targeted therapies. Here, we describe the development and testing of a CYP46A1-targeted positron emission tomography (PET) tracer, 18 F-CHL-2205 ( 18 F-Cholestify). Our data show that PET imaging readouts correlate with CYP46A1 protein expression and with the extent to which cholesterol is metabolized in the brain, as assessed by cross-species postmortem analyses of specimens from rodents, nonhuman primates, and humans. Proof of concept of in vivo efficacy is provided in the well-established 3xTg-AD murine model of Alzheimer’s disease (AD), where we show that the probe is sensitive to differences in brain cholesterol metabolism between 3xTg-AD mice and control animals. Furthermore, our clinical observations point toward a considerably higher baseline brain cholesterol clearance via CYP46A1 in women, as compared to age-matched men. These findings illustrate the vast potential of assessing brain cholesterol metabolism using PET and establish PET as a sensitive tool for noninvasive assessment of brain cholesterol homeostasis in the clinic.

Chronic Aripiprazole and Trazodone Polypharmacy Effects on Systemic and Brain Cholesterol Biosynthesis

“…The finding of elevated cholesterol-derived oxysterols in females, despite stable overall cholesterol levels, suggests baseline cholesterol turnover may be increased in females. Our findings agree with recently published work [ 70 ] showing a significantly higher baseline brain cholesterol clearance via CYP46A1 in women than in age-matched men. The observed male vs. female difference in 8-DHC can be attributed to the action of the X-linked EBP enzyme, while the origins of the other differences are unknown at the current time.…”

CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice

“…Our current work shows that gonadectomy leads to decreased Cyp46a1 expression in mice. Furthermore, a recent study has shown higher CYP46A1 levels in young, cognitively normal women in comparison to men, suggestive of a role for sex hormones in CYP46A1 regulation ( 72 ). Together, these findings encourage further investigation of the interplay between sex hormone levels, brain cholesterol turnover, and neurodegeneration in humans.…”

Evaluation of [18F]RoSMA-18-d6 as a CB2 PET Radioligand in Nonhuman Primates

“…Combined PET/CT studies and separate magnetic resonance imaging (MRI) studies were performed with two rhesus monkeys (male, 5.05–6.00 kg), as previously described. , After administering ketamine (10 mg/kg) via intramuscular injection for anesthesia, subjects were placed on the scanning bed in a supine position for brain T1-weighted MR anatomical images on a 3.0 T scanner (GE Discovery 750, Milwaukee). While MRI images were acquired without the need for inhalative anesthesia, PET studies required initial anesthesia with ketamine (10 mg/kg; i.m.…”