How to get proteins through the blood-brain barrier?

Until now, scientists assumed that the blood-brain barrier was a barely permeable barrier for substances from the blood. It was known, however, that their blocking effect decreases with age. However, as a U.S. team has now shown, more proteins cross the blood-brain barrier than previously thought. This could open up new approaches to the treatment of neurological diseases.(1)

Illustration of the most important cells of the brain: neurons (yellow); astrocytes (orange); oligodendrocytes (gray); microglia (white)

What enters the brain is strictly controlled

The brain is a highly complex network of countless different nerve cells. However, hormones, ions and other molecules from the bloodstream can disrupt this balance of electrical and chemical signal transmission between neurons, so their entry into neural tissue must be tightly regulated. In addition, the cells of the blood vessels in the brain form a particularly dense wall through which an uncontrolled diffusion of substances from the blood is not possible – the blood-brain barrier. In addition, these vessels are lined with a thick layer of protective and transport proteins. (1)

In particular, it is practically impossible for water-soluble substances to pass from the blood into the brain unless special channel proteins are available for them to cross the blood-brain barrier. In contrast, fat-soluble substances such as alcohol and nicotine or gases such as oxygen overcome this barrier more easily. What is an important protective function in healthy people presents researchers with enormous challenges if active substances for the therapy of neurological diseases are to reach the brain.

Latest research results refute important assumptions

As a team reported in the summer of 2020 in the renowned journal Nature, the blood-brain barrier is more permeable than previously assumed and tends to become more impermeable with increasing age – in other words, the exact opposite of the previous state of knowledge.(2)

As a model for the permeability of the blood-brain barrier, the team from Stanford University in California studied the distribution of certain proteins in the blood and brain of mice. In contrast to previous studies on the blood-brain barrier, however, the scientists did not resort to artificially supplied proteins, but instead used endogenous proteins, i.e., molecules that the mice produced themselves.

In a first step, they took some blood from the animals and labeled the proteins contained therein in the laboratory using the protein ligation technique. Then the proteins modified in this way were reinfused into the bloodstream of the mice. And then they determined the amount of labeled proteins in nerve tissue samples. This showed that significantly more proteins pass through the blood-brain barrier than had previously been assumed.

Type of transport changes with age

By analyzing the transport mechanisms in detail, it was possible to explain the reason for the permeability of the barrier and its decrease with age. Most of the endogenous proteins in the mice pass through the blood-brain barrier via specific receptors on the surface of vascular cells. After binding to the receptors, they are taken up into the cells along with their cargo, transported to the other side of the vascular walls, and released into the brain there. This process is also called transcytosis.

This receptor-mediated type of transport is dominant in younger mice. In older animals, however, the researchers found a decrease in this specific transport and increasingly a non-specific crossing of the blood-brain barrier, in which the cargo molecules are not bound via receptors but via random interactions with the cell surface and are then taken up. The unregulated influx of substances into the brain in old age could therefore also contribute to the development of neurological diseases, which occur more frequently with increasing age.

New opportunities for directed drug transport?

The authors of the study hope that knowledge of the two mechanisms will lead to new approaches for making the blood-brain barrier specifically surmountable for drug molecules. The transcytosis receptors that have now been identified could be used, for example, to transport antibodies against the amyloid fibrils formed in Alzheimer’s disease into the brain. For this purpose, the drug molecules could be packaged in nanoparticles that bind specifically to the receptors on the vascular cells. Such technologies are already being researched.(3) (4)

In addition, the study team suggests reducing nonspecific transcytosis in patients with neurological diseases to protect the brain from harmful substances in the bloodstream. But this first requires further experiments to investigate how transcytosis is regulated in the blood-brain barrier and, most importantly, whether the results of the animal model can be transferred to humans.

As part of the vfa initiative #ResearchOnStage explained the pharmaceutical researcher Dr. Christian Ried of AbbVie Germany gave a vivid and entertaining presentation to a large audience on how he uses systems that deliver nanoparticles by intravenous injection to the Blood-brain barrier and, with the help of active targeting, are transported beyond it into the brain.

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