Liver X receptor alpha ensures blood-brain barrier function by suppressing SNAI2

Area of Science:

• Neuroscience
• Vascular Biology
• Molecular Biology

Background:

• Alzheimer's disease (AD) often involves capillary cerebral amyloid-angiopathy (capCAA), leading to hypoxia, neuro-inflammation, and blood-brain barrier (BBB) dysfunction.
• AD patients exhibit increased vessel formation, suggesting reactivated angiogenesis, but the underlying molecular mechanisms remain unclear.
• The Liver X receptor (LXR) family, particularly LXRα, is known to inhibit angiogenesis and maintain BBB stability.

Purpose of the Study:

• To elucidate the regulatory mechanism of LXRα in preserving BBB integrity in human brain endothelial cells (BECs).
• To investigate the role of LXRα in pathological conditions like capCAA and hypoxia.
• To explore the association between LXRα, SNAI2, and vascular changes in AD.

Main Methods:

• Investigated LXRα's role in inhibiting SNAI2 in human BECs.
• Examined the impact of LXRα deletion on DLL4-NOTCH signaling in BECs.
• Analyzed vascular SNAI2 expression in the occipital cortex of AD patients with and without capCAA, correlating it with amyloid-beta and hypoxia markers.

Main Results:

• LXRα constitutively inhibits the transcription factor SNAI2, ensuring BEC identity and BBB integrity.
• LXRα deletion or hypoxia leads to decreased LXRα, increased SNAI2, impaired DLL4-NOTCH signaling, and BEC de-differentiation/sprouting.
• Vascular SNAI2 is elevated in AD patients with capCAA, correlating with amyloid-beta deposition and angiopoietin-like 4 (hypoxia marker).

Conclusions:

• LXRα is crucial for maintaining BEC identity, BBB stability, and preventing aberrant angiogenesis.
• A decrease in LXRα during hypoxia in capCAA vessels likely drives SNAI2 upregulation, leading to BBB dysfunction and sprouting.
• This study reveals a novel LXRα-SNAI2 pathway critical for vascular homeostasis in AD.