Proteins from the bloodstream reach specific brain cells through selective transport pathways, which may explain how this communication fails during the early stages of Alzheimer’s disease, News-Medical reported.
Scientists from institutions including Gladstone Institutes, the University of California, San Francisco, the Buck Institute for Research on Aging, and Emory University investigated how circulating molecules cross into the central nervous system. The brain is normally protected by the blood-brain barrier, which restricts the entry of most circulating substances and small-molecule drugs to maintain a stable environment.
Recent investigations show that proteins produced outside the nervous system heavily influence brain health and neurodegeneration. To map these dynamics, researchers developed a bioorthogonal proteomics approach using albumin-deficient mice injected intravenously with labeled plasma proteins.
Liquid chromatography-tandem mass spectrometry identified 191 plasma proteins interacting with brain vasculature, with 92 crossing into the brain parenchyma. These transported proteins originated predominantly from the liver, adipose tissue, and intestine, possessing specific molecular characteristics like higher lysine and alpha-helical content.
Specific proteins targeted distinct cell populations within the brain after crossing the vascular wall. Apolipoprotein A1 preferentially accumulated in astrocytes, while alpha-1 antitrypsin predominantly entered microglia.
Scavenger receptor class B type 1 mediated APOA1 uptake by brain endothelial cells before a receptor-mediated hand-off directed it toward astrocytic ATP-binding cassette transporter A1. This interaction upregulated pathways associated with cholesterol efflux and high-density lipoprotein particle assembly while downregulating lipid synthesis.
Medium collected from APOA1-treated astrocytes increased neuronal cholesterol levels, postsynaptic density protein 95 expression, and dendritic spine density in cell-culture experiments. Conversely, alpha-1 antitrypsin promoted a disease-associated microglial state and increased phagocytosis of experimental particles and amyloid-beta peptides.
Experiments comparing healthy wild-type mice, lipopolysaccharide-treated mice, and 18-week-old male 5xFAD Alzheimer’s disease models revealed distinct pathological disruptions. Early-stage disease models showed selective transport changes without widespread physical barrier breakdown, marked by decreased APOA1 uptake in astrocytes and increased SERPINA1 uptake in microglia.
Reduced levels of endothelial scavenger receptor class B type 1 and astrocytic ATP-binding cassette transporter A1 drove this impaired delivery. Increasing liver-derived APOA1 production using an adeno-associated virus vector raised APOA1 levels in the liver, blood, and brain of 5xFAD mice.
This increased availability reduced astrocytic lipid accumulation, glial fibrillary acidic protein levels, and brain interleukin-1 beta concentrations. It also decreased soluble vascular amyloid-beta 42 levels and hippocampal dentate gyrus plaque burden while increasing synaptic density in the hippocampus and cortex.
Behavioral assessments demonstrated reduced hyperactivity and improved preference for a novel arm following the vector treatment, indicating better spatial memory. Novel-object preference improved, whereas novel-place recognition did not change significantly. The proteomics screen may have missed some proteins, and the role of astrocytic ABCA1 in living mice remains uncertain.
Further investigations are required to determine whether these transport mechanisms and treatment effects translate to humans and other neurological disorders, particularly regarding advanced disease stages.
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