Scavenger Receptor Class B Type 1 (SCARB1, also known as SR-BI) is a member of the scavenger receptor family that mediates selective uptake of cholesterol from HDL and other lipoproteins. In the brain, SCARB1 is expressed on endothelial cells and microglia, where it plays important roles in cholesterol homeostasis, Aβ clearance, and neuroinflammation.
SCARB1 is a 509-amino acid glycoprotein with a complex topology:
- N-terminal extracellular domain: Large extracellular loop (~400 aa) containing the ligand-binding site
- C-terminal transmembrane domain: Two transmembrane helices
- Cytoplasmic tails: Short N- and C-terminal cytoplasmic domains
The extracellular domain contains multiple scavenger receptor cysteine-rich (SRCR) domains.
In the nervous system:
- Cholesterol efflux: Mediates reverse cholesterol transport from peripheral tissues
- HDL binding: Primary receptor for HDL cholesterol uptake
- Blood-brain barrier function: Expressed on brain microvascular endothelial cells
- Microglial function: Involved in phagocytosis and lipid metabolism in microglia
- SCARB1 mediates uptake of Aβ by microglia and astrocytes
- Polymorphisms in SCARB1 associated with AD risk
- Involved in HDL-mediated Aβ clearance from the brain
- Deletion of SCARB1 leads to increased Aβ accumulation in mouse models
- Acts as a co-receptor for Aβ internalization
- SCARB1 regulates Aβ clearance across the blood-brain barrier
- Important for vascular Aβ deposition and clearance
- Modulates microglial inflammatory responses to Aβ
- SCARB1 deficiency leads to increased neuroinflammation
Targeting SCARB1 for AD therapy:
- SCARB1 agonists to enhance Aβ clearance
- HDL mimetics to promote SCARB1-mediated Aβ clearance
- Gene therapy to increase SCARB1 expression in brain
- SCARB1 and Aβ clearance (Zhou et al., 2021)
- SCARB1 in brain cholesterol homeostasis (Wang et al., 2019)
- HDL and Aβ clearance via SCARB1 (Kim et al., 2022)