“The brain is getting worse and worse” is one of the most frightening and helpless characteristics of aging. Keeping the brain young is the wish of countless people and the goal of many researchers. Recently, scientists at the University of California, Berkeley, in collaboration with Ben-Gurion University in Israel, published two papers suggesting a key role in aging’s cognitive ability: the blood-brain barrier.
在动物实验中，研究者修复血脑屏障“渗漏”引起的问题后，成功改善了小鼠的记忆和学习能力。鉴于血脑屏障在衰老过程中有着过去未知的重要性，最新一期《科学》子刊Science Translational Medicine以封面故事的形式介绍了这组工作。
Photo credit: AAAS; Author: GUNilla ELAM
The blood-brain barrier, as the name suggests, is a barrier between blood flow and brain tissue, which regulates the communication between the vascular system and the brain. We know that the brain is a very energy-hungry organ, so there are many blood vessels in the brain to provide enough oxygen and energy. But there are also substances in the blood stream that brain cells don’t need, or even try to avoid, such as some inflammatory factors. The blood-brain barrier, which is made up of vascular endothelial cells, peripheral cells and astrocytes, plays an important role in filtration.
Professor Alon Friedman and colleagues have developed a special magnetic resonance imaging (MRI) technique to detect the blood-brain barrier. They found that nearly 60 percent of people over the age of 70 had a “leakage” problem with the brain filtration system. Moreover, people with severe cognitive impairment, such as alzheimer’s patients, have more severe leakage of the blood-brain barrier.
Dust masks are broken, and the particles that should be blocked are inhaled into the body; similarly, when the brain’s filtration system leaks, chemicals in the blood that can cause inflammation and cell death can enter brain tissue.
In albumin, for example, the protein is usually dissolved in the serum and blocked by the blood-brain barrier. After a brain trauma, albumin seeps into the brain, triggering a series of inflammatory reactions that cause abnormal excitement in the neural circuits. This is also a reason why people with traumatic brain injury are prone to seizures.
In the study, Professor Daniela Kaufer and colleagues analyzed samples of human brain tissue and found that the changes in the brain caused by aging were similar to trauma. The amount of albumin in the aging brain tissue has also increased, strengthening nerve inflammation.
The results of MRI show edifying blood-brain barriers in both humans and mice as they age (Photo: Supplied)
Professor Kaufer speculates that the “inflammatory haze” caused by leakage of the blood-brain barrier may be an important factor affecting the function of the aging brain. To do this, they tested the idea on mice.
They simulated a blood-brain barrier leak and injected albumin into the brains of young mice. In just one week, the young brain “gets old”. “We reproduced the brain’s aging process through gene expression, inflammatory responses, resilience to induced epilepsy, post-epileptic mortality, and maze performance. Professor Kaufer said, “And, these are related to the specific location where we inject the protein.” “
The results of a set of experiments that operate on the contrary are even more impressive.
Molecular-level studies showed that in the brains of older mice, albumin activates TGF-beta signals in astrocytes, which in turn causes cognitive impairment. Professor Barry Hart, a drug chemist in the research team, has synthesized a small molecule drug that specifically blocks TGF-beta receptors in astrocytes and reduces signal activity levels. So the researchers gave the drug to older mice.
The brains of older mice showed encouraging changes: gene expression was more similar to that of the younger brain, inflammation decreased, the rhythm of electroencephalopathy was more stable, and the frequency of epilepsy was reduced. In addition, after taking the drug, the spatial cognitive ability to find a way in the maze also recovered significantly, comparable to that of young mice who were only half the age!
“When the ‘inflammatory haze’ is removed, the aging brain is like a young brain for a few days. The study authors concluded, “This is a very optimistic finding in terms of the plasticity of the brain. We can reverse brain aging! “
The MRI results (left) show edified patients with severe leakage of the blood-brain barrier, and correspondingly their electroencephalogram results (right) indicate that typical bursts of slow-wave eventised activity in AD patients are also more frequent (Photo: Resources 2)
Based on these results, the researchers suggest that combining MRI and electroencephalograms could help doctors monitor the patient’s blood-brain barrier and then intervene with the drug.
“We now have two biomarkers that can pinpoint exactly where the blood-brain barrier is leaking, so doctors can identify patients who need treatment and determine how long the drug will take, ” he said. Professor Kaufer said, “You can track the patient’s condition and stop taking the drug until the blood-brain barrier heals.” “
Professors Alon Friedman and Daniela Kaufer, co-authors of the two studies, have been working together for more than two decades to determine the role of the blood-brain barrier in brain disease (Photo: UC Berkeley website)
Currently, Professor Kaufer, Professor Friedman and Professor Hart have started a company to develop clinically available drugs to repair blood-brain barrier leakage. They hope that this will not only help patients with stroke, concussion or brain trauma to reduce inflammation in the brain, but will eventually help AD patients or other dementia sufferers who sit through the blood-brain barrier.