ApoE (Apolipoprotein E) in Brain Pericytes Regulates Endothelial Function in an Isoform-Dependent Manner by...

Area of Science:

• Neuroscience
• Genetics
• Vascular Biology

Background:

• The ε4 allele of the apolipoprotein E gene (APOE4) is a significant genetic risk factor for Alzheimer's disease.
• While apoE4's role in amyloid pathology is studied, its impact on amyloid-independent pathways, especially cerebrovascular integrity, remains less understood.

Purpose of the Study:

• To investigate the effects of different apolipoprotein E (apoE) isoforms on brain pericyte function and cerebrovascular integrity.
• To determine if apoE4 impairs pericyte-mediated modulation of endothelial cells.

Main Methods:

• Coculturing endothelial cells with pericytes from apoE4-targeted replacement (TR) mice and apoE3-TR mice.
• Assessing extracellular matrix protein induction, tube-like structure formation, and barrier formation in endothelial cells.
• Analyzing extracellular matrix protein expression and plasma protein leakage in aged apoE4-TR and apoE3-TR mice.

Main Results:

• Endothelial cells cocultured with apoE4 pericytes showed reduced extracellular matrix protein induction, tube-like structure formation, and barrier formation compared to those with apoE3 pericytes.
• Aged apoE4-TR mice exhibited decreased extracellular matrix protein expression.
• Aged apoE4-TR mice demonstrated increased plasma protein leakage across the blood-brain barrier.

Conclusions:

• Apolipoprotein E4 impairs pericyte-mediated basement membrane formation.
• These findings suggest that apoE4 contributes to cerebrovascular dysfunction through mechanisms independent of amyloid pathology.