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Credit: K. H. Fung/SPL
For decades, scientists thought of the blood–brain barrier as an impenetrable layer. Overtime that view has changed, as researchers realized the barrier was more permeable than first thought. Now a team have catalogued almost 100 proteins that can pass through it to maintain brain health.1
The team also found that the transport of some of these crucial proteins breaks down in mice with brain disease that mimic early-stage Alzheimer’s disease.
“The paradigm in the field has been that the blood–brain barrier is normally impermeable and then becomes leaky as a result of Alzheimer’s disease,” says study co-author Andrew Yang, a neuroscientist at Gladstone Institute of Neurological Disease in San Francisco, California. Instead, his team’s work suggests that the blood–brain barrier actively imports proteins that the brain needs to function and the loss of these proteins drives the dysfunction seen early in the disease, he adds.
Labelling proteins
Yang and his colleagues developed a technique to label a large array of proteins in the blood and track those that can enter the brain. Of the 861 proteins they mapped, 92 crossed the blood–brain barrier into the brain. Most of these proteins were produced in distant organs, particularly the liver.
The team focused on apolipoprotein A1 (APOA1) which has been linked to potential protective effects against Alzheimer’s disease. Once inside the brain, APOA1 stimulates brain cells called astrocytes to release cholesterol, which is important for maintaining the synapses through which neurons communicate. But how the protein crossed the blood-brain barrier has been unclear until now, says Yang.
His team found that two receptors for APOA1 — SR-B1 and ABCA1 — are present on the blood–brain barrier as well as astrocytes. This suggests how the protein moves from the blood-brain barrier to the specific brain cells that need them, the authors say.
When Yang’s team blocked the ABCA1 receptor in laboratory-grown astrocytes, the protein no longer had the same cholesterol-regulating effects.
Alzheimer’s link
Scientists have long known that the blood–brain barrier breaks down as Alzheimer’s advances, letting harmful molecules leak into the brain. Yang’s team found that a different problem emerges first.
Using their labelling technique in a mouse model of Alzheimer’s disease, the researchers found that the blood–brain barrier stopped importing protective proteins such as APOA1 into the brain before the barrier began to break down. This disruption to the protein transport was accompanied by a loss of neuronal connections, behavioural changes and other early hallmarks of the disease.
Yang and the team wondered whether increasing the supply of APOA1 in the blood might help to counter some of the damage caused by Alzheimer’s disease. To find out, the team engineered mice with Alzheimer’s to produce extra APOA1 in the liver. When more APOA1 crossed their blood–brain barrier and entered the brain, the mice showed fewer Alzheimer’s-disease-related markers. For example, they had reduced fat build-up in astrocytes and lower levels of inflammatory molecules.
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doi: https://doi.org/10.1038/d41586-026-03655-2
References
- Zhou, H. et al. Cell https://doi.org/10.1016/j.cell.2026.10.039 (2026).Article Google Scholar
Zhou, H. et al. Cell https://doi.org/10.1016/j.cell.2026.10.039 (2026).
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