How the molecular pump works

With the help of a radioactive label, scientists traced how the brain gets rid of cholesterol

Mikhail Orlov, Naked Science

Disorders of cholesterol metabolism are associated with the development of a number of diseases — not only the cardiovascular system, but also, say, affecting the brain. Cholesterol metabolism in this organ is very complicated, but the removal of this substance from neurons is considered especially important. It is carried out by an enzyme-cytochrome P450 46A1 — one of the many cytochromes that works precisely in the nervous system.

This enzyme is also called cholesterol-24S-hydroxylase, or CYP46A1. It catalyzes the conversion of cholesterol into 24S-hydroxycholesterol and thereby contributes to its removal.

It is important for doctors and scientists to know how intensively the brain gets rid of cholesterol and how various external factors affect it. However, previously, they did not have methods for visualizing the concentration of this important metabolite in the brain.

The gap was filled by the authors of a new article in Science Translational Medicine (Haider et al., Assessment of cholesterol homeostasis in the living human brain), a large international team of researchers. They have created and successfully tested a new molecular label that specifically binds CYP46A1 and is suitable for imaging the activity of this enzyme using positron emission tomography (PET).

The label was named 18F-Cholestify (18F-Cholestify, 18F-CHL-2205). This small molecule contains the easily traceable radioisotope fluoro-18 — it binds strongly and selectively to the active center of cytochrome CYP46A1.

Using a radioactive signal from fluorine-18 (using the autoradiography method) and Western blotting, the researchers found that after the introduction of 18F-Cholesterol penetrates well into the brains of mice, rats and rhesus monkeys. The label accumulates especially actively in the cerebral cortex, the hippocampus and such anatomical structures of the brain as the shell and caudate nucleus.

At the same time, in the brains of mice with the cytochrome CYP46A1 gene knocked out (that is, "turned off") or after chemical inhibition of the enzyme 18F-Cholesterol was almost not delayed.

The authors of the study also tested the new label on humans. Four men and four women aged 22-31 were injected with 18F-Cholesterol and had their brains PET. The label molecule accumulated well in the cerebral cortex, thalamus and basal ganglia - those parts of the brain where cytochrome CYP46A1 is expressed especially strongly.

It is known that in people with moderate cognitive impairments (which can signal the onset of the disease, including Alzheimer's disease), the level of the cholesterol metabolite — 24-hydroxycholesterol, as well as a special pathological form of tau protein (p-tau181) increases in the cerebrospinal fluid.

The new technique will effectively visualize the first signs of an approaching disease directly in the brain, long before the first symptoms appear and with good detail.

"Previously, we could only note the activity of CYP46A1 by measuring the concentration of 24-hydroxycholesterol in the cerebrospinal fluid; now a new ligand (a molecule with a specific binding. — Editor's note) will allow researchers to obtain a map of its spatial distribution in the brain," he said Mikael Simons from the Technical University of Munich (Germany).

The scientist believes that the high rate of cholesterol metabolism in transgenic mice serving as a model of Alzheimer's disease (animals of the 3xTg line) may be associated with a neurodegenerative process in their brain. The resulting death of neurons leads to the destruction of cell membranes, which are known to contain large amounts of cholesterol. It gets out, and cytochrome CYP46A1 has to get rid of it more actively.

The researchers also noted curious sex differences in the distribution of 18F-Cholesterol. It turns out that in the shell and caudate nucleus of the female brain, the label accumulated faster — apparently, this is due to the higher rate of cholesterol metabolism in the norm.

Compared to the male participant (right), the female volunteer (left) had a higher absorption of the 18F-Cholesterol label in the shell (black arrow) and caudate nucleus (white arrow). Figure from the article by Haider et al. – VM.

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