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A new study in mice has found that the blood-brain barrier not only prevents harmful substances from entering the brain but also selects beneficial proteins produced elsewhere in the body and delivers them to specific brain cells. The mechanism may be disrupted in the early stages of Alzheimer’s disease, potentially creating a new target for treatment.
Researchers at the Gladstone Institutes in San Francisco say the finding could shift attention in Alzheimer’s treatment beyond the brain to processes taking place elsewhere in the body. AnewZ reports.
The blood-brain barrier is a network of specialized cells lining the inner surfaces of brain blood vessels and separating the brain from the rest of the bloodstream. Study leader Andrew Yang of the Gladstone Institutes said scientists had long viewed the barrier as a simple physical boundary protecting the brain from toxins. The new findings, he said, show it is an active system that selects suitable proteins in the blood and carries them to matching cells in the brain.
In the study, scientists used Nobel Prize-winning protein-labeling chemistry to track 861 proteins in mice without altering their functions. After the labeled proteins were injected back into the mice, the researchers examined brain tissue to identify which proteins had crossed the barrier.
The study was published in the journal Cell on November 11. Yang was the senior author, while Haoyue Zhou, a researcher in his laboratory, was the lead author. Scientists from the University of California, San Francisco; the Buck Institute for Research on Aging; the Hong Kong Center for Neurodegenerative Diseases; the Hong Kong University of Science and Technology; and Emory School of Medicine also took part.
Only 92 of the 861 tracked proteins crossed the blood-brain barrier. Most were produced in distant parts of the body, particularly the liver. According to the Gladstone Institutes, the barrier recognizes and transports selected proteins using specialized receptors; the proteins do not enter the brain at random. After crossing the barrier, they are delivered to different types of brain cells.
The researchers identified apolipoprotein A1 (APOA1), produced in the liver, as a particularly important protein. It crosses into the brain and reaches astrocytes, which help maintain healthy connections between neurons.
The scientists also studied mice with a form of Alzheimer’s disease to investigate disruption of the protein transport mechanism. When the barrier stopped transporting APOA1, the resulting deficiency was linked to the loss of connections between neurons, behavioral changes and other early signs of the disease.
The researchers found that the transport of protective proteins such as APOA1 stopped before the barrier began allowing harmful substances into the brain. This suggests that a failure in the brain’s protein supply system may arise before the more widely recognized breakdown of the barrier.
In another experiment, genetically modified mice whose livers produced more APOA1 showed increased transport of the protein into the brain and fewer signs of Alzheimer’s disease. Yang said the disease may not begin entirely within the brain, but could be linked to an interruption in the supply line from the body to the brain.
The findings raise the possibility of treating Alzheimer’s disease by increasing the production of protective proteins elsewhere in the body. Yang said it may be possible to tackle the disease outside the brain by restoring proteins the brain has lost.
The researchers outlined three possible approaches: increasing the production of protective proteins in organs such as the liver; using the barrier’s natural targeting system to direct treatments to specific brain cells; and developing a new generation of delivery systems that use the barrier’s transport mechanism to carry drugs into the brain.
Yang said the study maps the proteins the brain needs from the body and the system that transports them. He said he hopes the findings will lead to new Alzheimer’s treatments and a new generation of systems for delivering drugs to the brain.
The research is at an early stage and has so far been conducted only in mice. It is not yet known whether the same protein transport disruptions occur in people with Alzheimer’s disease, or whether restoring the supply could prevent the disease or slow its progression. The study also does not prove that disruption of the protein supply is an initial cause of Alzheimer’s disease; Yang presented this as a possibility, not an established finding.
