Ninety-two circulating proteins cross the blood-brain barrier and enter the brain parenchyma, according to a study published in the journal Cell.
Protein Transport Pathways
Researchers characterized blood-to-brain protein transport and identified alterations in Alzheimer’s disease models. The study was carried out by investigators at the Gladstone Institutes, the University of California, San Francisco, the Buck Institute for Research on Aging, and Emory University. Their work involved a partnership with the Hong Kong Center for Neurodegenerative Diseases alongside the Hong Kong University of Science and Technology.
The blood-brain barrier restricts circulating substances while regulating necessary proteins. More than 98% of small-molecule drugs cannot cross this barrier, creating challenges for neurological therapies. Proteins produced outside the central nervous system influence neurodegeneration, yet their transport pathways remain incompletely understood.
Proteomic Analysis Methods
The team developed a bioorthogonal proteomics approach to identify circulating proteins entering the brain. Plasma proteins from albumin-deficient mice were labeled with trans-cyclooctene and injected intravenously into wild-type mice three times over six hours. Liquid chromatography-tandem mass spectrometry identified proteins in brain vessels and brain parenchyma.
The proteomic screen identified 191 plasma proteins that interacted with the brain vasculature. Ninety-two proteins crossed the barrier into the brain parenchyma, while 99 were detected only in vessels. Another 670 proteins showed no detectable barrier interaction.
Cellular Uptake Mechanisms
Transported proteins originated mainly from the liver, adipose tissue, and intestine. Apolipoprotein A1 preferentially accumulated in astrocytes, whereas alpha-1 antitrypsin predominantly entered microglia. Scavenger receptor class B type 1 mediated APOA1 uptake by brain endothelial cells.
“APOA1 preferentially accumulated in astrocytes, whereas alpha-1 antitrypsin predominantly entered microglia,” the researchers said in the study.
After crossing the barrier, APOA1 interacted with astrocytic ATP-binding cassette transporter A1. This receptor-mediated hand-off directed APOA1 toward astrocytes. APOA1 treatment altered astrocytic gene expression and reduced intracellular lipid levels.
Alzheimer Model Disruptions
Early-stage 5xFAD mice showed selective transport changes without widespread physical barrier disruption. APOA1 uptake decreased, especially in astrocytes, and SERPINA1 uptake increased in microglia. Reduced scavenger receptor class B type 1 and reduced astrocytic transporter levels impaired APOA1 delivery.
Increasing liver-derived APOA1 production raised its levels in the liver, blood, and brain. Astrocytic lipid accumulation and glial fibrillary acidic protein levels decreased, along with brain interleukin-1 beta concentrations. Synaptic density increased in the hippocampus and cortex.
How Plasma Proteins Interact with Brain Vasculature
How many plasma proteins interacted with the brain vasculature in the study?
The proteomic analysis identified 191 plasma proteins that interacted with the brain vasculature under the experimental conditions.
Which organs were the primary source of the transported proteins?
The transported proteins originated predominantly from the liver, adipose tissue, and intestine.
What receptor mediated APOA1 uptake by brain endothelial cells?
Scavenger receptor class B type 1 mediated APOA1 uptake by brain endothelial cells before its hand-off to astrocytes.
Which mouse model was used to study early-stage Alzheimer disease pathology?
The researchers used 18-week-old male 5xFAD mice to study disease-associated pathological changes.