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

(ORDO NEWS) — Positron emission tomography, together with the new molecular label 18F-Cholestify, was used for the first time to visualize the process of removing cholesterol from the human brain.

This new tool will be useful for studying the mechanisms of development of neurological disorders, including Alzheimer’s disease, as well as finding methods for their treatment.

Cholesterol metabolism disorders are associated with the development of a number of diseases – not only the cardiovascular system, but also, say, affecting the brain.

The exchange of cholesterol in this organ is very complicated, but the removal of this substance from neurons is considered especially important. It is carried out by the enzyme cytochrome P450 46A1 – one of the many cytochromes that works specifically in the nervous system.

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

It is important for doctors and scientists to know how intensively the brain gets rid of cholesterol and how various external factors influence this. However, they had no previous 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 , a large international team of researchers. They 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 fluorine-18, which binds strongly and selectively to the active site of the cytochrome CYP46A1.

Using a radioactive signal from fluorine-18 (using the method of autoradiography ) and Western blotting , the researchers found that after administration of 18F-cholestify, it penetrates well into the brains of mice, rats and rhesus monkeys.

The label is especially actively accumulated in the cerebral cortex, the hippocampus, and such anatomical structures of the brain as the putamen and caudate nucleus.

Using a radioactive label scientists traced how the brain gets rid of cholesterol 2
Molecule structure of 18F-Cholestify

At the same time, in the brains of mice with a knockout (i.e., “turned off”) CYP46A1 cytochrome gene or after chemical inhibition of the 18F enzyme, Cholestiphium almost did not linger.

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

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

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.

“Before, 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 specific binding.

Will allow researchers to map its spatial distribution in the brain,” 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 (3xTg animal lines) 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 outside, and the cytochrome CYP46A1 has to get rid of it more actively.

The researchers also noted curious sex differences in the distribution of 18F-Cholestiphae. 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.

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