Can we reverse aging by plugging our "brain holes"?

After the Gulf War, some soldiers who suffered physical and psychological stress experienced unexplained cognitive decline.

Subsequent research pinpointed the source of the disease on the loopholes in the blood-brain barrier.

In fact, as people get older, more and more holes will appear in the brain of ordinary people.

These loopholes can cause some of the proteins in the blood to enter the brain, causing inflammation and cognitive decline.

In this excerpt from the June issue of "Global Science", two scientists accidentally discovered in decades of experiments: patching loopholes may reverse aging and regain youth in the brain.

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Written article | Daniela Kaufer, Alon Friedman (Translated by Alon Friedman)Zhuang Lingna was in 1994, one in Jerusalem In the cold late night, the two of us (Caufer and Friedman) squatted by the pool of cold water in the Hebrew University laboratory and watched the mice swimming carefully.

It was cold in the laboratory, long-term bending made our backs sore, and repeated experiments over many nights made us exhausted.

Of course, mice feel the same as us, because they don’t like swimming, especially in cold water, but we have to put them under such pressure.

We and the mice get together every night to unravel an unsolved medical mystery: Gulf War syndrome.

In 1991, after the Gulf War ended, more and more reports stated that the soldiers of the multinational force led by the United States were suffering from chronic fatigue, muscle pain, sleep disturbance and cognitive decline, and the hospitalization rate of these soldiers was also Higher than other soldiers.

Some doctors suspect that bropistigmine (a drug that soldiers would take) could cause these diseases if it gets into the brain.

But there is a problem with this theory: Bropistigmine in the blood should not be present in the brain.

The walls of blood vessels in the brain are made up of special cells, which are arranged closely together to form a "wall" that can control the entry and exit of substances.

This city wall is called the blood-brain barrier, and its existence prevents toxins, pathogens (such as bacteria) and most drugs from passing through.

However, there is a possibility that the blood-brain barrier of these sick soldiers is not so complete, and they have lost the ability to control the entry of drugs.

We want to know whether the physical and mental stress brought by the war to the soldiers will cause damage to the blood-brain barrier to some extent, so we chose to force the mice to swim to test our ideas.

After the mice finished swimming, we took them out of the pool and injected some blue dye into their veins.

After the dye was transported to various parts of the mouse body and stained it blue, we euthanized the mice and then observed their brains under a dissecting microscope.

If the blood-brain barrier of the mouse is intact, then the brain should remain normal pink or white.

For several consecutive nights, we tried to set multiple swimming durations, but we didn't find any abnormality in the color of the mouse brain.

However, on one night, after the mice were immersed in slightly cooler water twice, the situation looked a little different.
The brains of these mice showed a distinct blue color.

At that moment, we couldn't help but jump up, dancing with excitement.

Laboratory work is usually tedious, but success is often so subtle.

Our weird experiment was successful, and it shows that high stress may cause a leak in the blood-brain barrier.

With the help of our mentor, neuroscientist Hermona Soreq, we have further demonstrated that this change in the blood-brain barrier allows bropistigmine to enter the brain and change the activity of brain cells.

In two papers published in Science Translational Medicine in 2019, we proved that as people age, the blood-brain barrier loses its integrity and leaks, so that the blood cannot enter the brain under normal circumstances.
Proteins break through defenses, and these accidental intrusion proteins will further activate a series of chain events between brain cells, resulting in some common and significant changes associated with aging and diseases, such as inflammation, abnormal neuronal activity, and cognitive impairment.

The causal relationship between the loopholes in the blood-brain barrier and these diseases seems very obvious, because at least in mice, trying to prevent the response caused by these loopholes can reverse the symptoms of the disease.

In older mice, we can prevent these cells from releasing inflammatory factors through genetic modification, or we can use targeted drugs that protect brain cells from blood protein stimulation to eliminate inflammation.

In addition, we used imaging technology to compare the brains of Alzheimer's patients with the brains of healthy people.

The imaging results show that people with the disease have excessive and progressive blood-brain barrier leaks, as well as other cascade reaction characteristics related to the disease.

Aging of the blood-brain barrier: The results of brain scans show that with age, there will be more and more holes in the blood-brain barrier.

There are no leaks in the blood-brain barrier at the age of 30 (1).

At the age of 42, the appearance of blue spots indicates a small number of holes in the blood-brain barrier (2).

At the age of 65, red and yellow spots represent the appearance of more vulnerabilities (3).

At the age of 76, the vulnerability of the blood-brain barrier continues to increase (4).

We do not know whether the destruction of the blood-brain barrier actually causes Alzheimer's disease or other brain diseases.

It may play a role in disease occurrence along with other factors, including genetic factors and various cell problems observed in brain aging.

The word blood-brain barrier sounds like a wall surrounding the brain, but in reality, it is more like a filter scattered throughout the brain.

The brain gets 15% to 20% of the oxygen-rich blood pumped by the heart through the complex network of blood vessels.

These blood vessels look very different from blood vessels in other parts of the human body.
Their walls are composed of tightly packed cells and have a specific molecular transport system that can form a semi-permeable filter.

As early as the 1990s, when we completed preliminary work on Gulf War syndrome, we discovered that other researchers had noticed that patients with certain brain diseases (including Alzheimer's disease) had blood-brain barrier damage.

But we don't know whether the damage of the blood-brain barrier is the cause or the result of these brain diseases, how the breach of the blood-brain barrier started, and how it will change the brain function.

We are eager to find answers to these questions.

Many patients with neurological diseases have defects in the blood-brain barrier, so what happens in the damaged blood-brain barrier? To find out, we treated the rats with a chemical that would make the blood-brain barrier form holes.

After the treatment, we will dissect the rat brain and slice it, put the slices in a nutrient solution to keep it alive, and record the electrical signals of the interconnections between the cells.

There was no abnormality in the neural signal recording of the previous few days.
The neurons were all intermittently sending electrical signals to each other in an irregular manner.

On the fifth day, when we almost decided to give up recording, the electrical signal changed: more and more neurons began to send out signals simultaneously.

For the next week, we stimulated these cells with electrodes, simulating brief electrical signals appearing in the cerebral cortex.

Unexpectedly, this stimulus caused a large number of cells to produce electrical signals at the same time, similar to what is observed in people and animals with epileptic seizures.

In fact, when we destroy the blood-brain barrier, the neurons in the brain are not immediately confused.
It takes about a week for them to re-establish a new network of connections.
At this time, just a small stimulus can trigger a scene.
Huge electric signal storm.

We call this pattern paroxysmal slow-wave events, similar to those observed in the brains of patients with Alzheimer's disease or epilepsy.

We only observed this electrical signal storm when the blood-brain barrier was destroyed, and normal brain slices would not be affected by electrical stimulation.

Therefore, we proposed a hypothesis: certain components in the blood penetrate the blood-brain barrier and reach these neurons to trigger this response.

We then injected blood directly into the brains of young healthy rats (by bypassing the blood-brain barrier) and monitored their electrical signal activity.

A few days later, we saw this electric signal storm again.

Obviously, the generation of this electrical signal storm is related to blood.

But blood is a very complex fluid, which contains many different types of cells and proteins.

In order to find the culprit that caused this storm, we conducted a lot of screening tests.

In the end, we discovered a blood protein that can cause this electrical signal disorder: albumin.

At the time, the troublesome protein, we were not very excited about this discovery.

What we hope to see is a very rare ingredient, but albumin is very common, and it can be seen in many body functions, so it is difficult for us to distinguish what albumin does in the electric signal storm.

However, we had no choice but to bite the bullet and start researching it.

The first thing we learned from research is that albumin seems to activate astrocytes after entering the brain, which is a key brain cell that provides structural and chemical support for neurons and their connections.

After albumin contacts astrocytes, it binds to transforming growth factor beta (TGF-beta) receptors on it.

Normally, TGF-β can activate astrocytes and microglia, thereby triggering an inflammatory response.

Local inflammation is a way for the brain to limit damage by destroying abnormally functioning cells.

However, if albumin continues to infiltrate, astrocytes and microglia will be over-stimulated, which will release excessive chemicals and cause harmful effects, including large amounts of TGF-β.

This phenomenon will damage many brain cells, change key neural circuits, and cause brain function degradation.

This destructive cascade also appeared in the brains of aging mice.

We selected a group of mice to live normally until they age, and observe their brains at various points in time.

It was found that albumin was not found in the brains of young mice, and albumin generally began to appear in the brains of middle-aged mice.

At first, this phenomenon was not obvious, but the integrity of the blood-brain barrier has been significantly reduced by this time, and it has become worse as the mice age.

At the same time, we found that compared with normal mice, the memory of mice with albumin in the brain was significantly reduced.

In the past 5 years, we have obtained enough evidence that this process also occurs in humans.

We used tracer molecules to mark the blood-brain barrier vulnerability signals of people in their 20s to 70s.

Through magnetic resonance imaging, we can see that as people age, the holes in the blood-brain barrier will gradually increase.

Brain regeneration Next, we tried to reverse this result in mouse experiments.

Although we cannot prevent albumin from penetrating the blood-brain barrier, we can prevent the TGF-β cascade triggered by the entry of albumin into the brain.

To this end, we have constructed a special mouse model in which the genes encoding TGF-β receptors have been artificially knocked out in their astrocytes.

These mice and the control group were implanted with a miniature pump that injected albumin into their brains when they were young.

Then we conducted a water maze test on the two groups of mice.
The results showed that the mice in the control group had difficulty completing the water maze task; but the mice whose TGF-β receptor was knocked out behaved like young, healthy mice.
Similarly, they can swim in the maze quickly and accurately, and when we change the configuration of the maze, they can also learn new routes.

By observing their brains, we found that these mice have low levels of inflammation and abnormal brain electrical activity.

This result is indeed encouraging.

But for humans, knocking out a gene that has a normal function in the brain is still not feasible.

However, there may be a drug that can achieve this effect.

Barry Hart, a medicinal chemist from Innovation Pathways, an emerging drug company in California, designed an anti-cancer drug that specifically blocks the activity of TGF-β receptors.

Hart got in touch with us and suggested that we try a drug called IPW on a mouse model.

When we administered the drug to middle-aged mice that began to leak albumin, their brains appeared younger.

The activity of TGF-β in the brains of these mice fell to the levels observed in young mice, and the levels of inflammation markers, abnormal electrical activity, and susceptibility to seizures were reduced.

But the biggest surprise comes from behavioral and cognitive testing.

We selected a group of old mice and let them traverse a whole new maze.

Some of the old mice received IPW treatment, and some did not.

We did not anticipate that IPW treatment would bring a lot of improvement, because we believe that the brains of elderly mice have been irreversibly damaged.

However, within a few days, the ability of the treated old mice to learn the maze can be equal to that of mice that are only half their age.

The untreated mice performed poorly in the maze as usual.

At this moment, the haze of inflammation seemed to dissipate, and the brain regained its youth.

Our intervention studies may show that the aging brain has the ability to recover from damage without a large number of cell deaths.

The world population is facing aging, and the number of people suffering from dementia and Alzheimer's disease is on the rise.

Unfortunately, neuroscientists do not know much about the early trigger mechanism of this transition from a young, healthy brain to a dysfunctional aging brain.

Alzheimer's disease and other neurological aging diseases are complex and may have many causes.

Now we know that the vulnerability of the blood-brain barrier should be one of them.

This theory provides a very intuitive new model that allows us to understand why brain function declines with age.

At the same time, this model also brings us more confidence, because our research results strongly suggest that the aging brain retains the ability to reshape and recover itself.

This ability may be inhibited due to the breach of the blood-brain barrier and subsequent cascading reactions, but it will not be irreversibly lost.

For us and other scientists, the next step is to find suitable ways to reduce the loopholes in the blood-brain barrier.

If we can figure out these things, I think we have the opportunity to make a meaningful contribution to many people.

The June issue of "Global Science" is now available.
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