Deficiency in N-cadherin-Akt3 signaling impairs the blood-brain barrier.

The blood-brain barrier (BBB) restricts the passage of protein-rich fluids through tight junctions (TJs) formed between brain endothelial cells (BECs). BBB restrictiveness diminishes with aging, but the underlying mechanisms remain unclear. BECs establish physical contact with pericytes via N-cadherin homophilic adhesion. In cortex tissue from young and middle-aged patients, the age-related loss of vascular N-cadherin corresponds with the disruption of occludin TJs. Genetic deletion of N-cadherin in ECs impairs occludin TJs, leading to reduced cerebral tissue perfusion and spatial memory deficit. Mechanistically, the assembly of N-cadherin contacts stabilizes occludin TJs via the phosphoinositide 3-kinase p110β-Akt3 circuit, which is disrupted with aging. Furthermore, mutation of occludin Ser471 to Ala destabilizes occludin TJs even in the presence of N-cadherin contacts. These findings highlight a functional role for N-cadherin as a signaling hub that stabilizes occludin at TJs in a phosphorylation-dependent manner, thereby supporting BBB integrity.