N-cadherin Adhesion-Mediated Signaling Supports the Blood-Brain Barrier and Cognitive Function

The blood-brain barrier (BBB) serves as a protective interface between the systemic circulation and the brain parenchyma, limiting the passage of toxins and protein-rich fluid into the central nervous system through brain endothelial tight junctions. The restrictive function of the BBB progressively declines with physiological aging. Brain endothelial cells form physical junctions with pericytes through N-cadherin, which support endothelial barrier integrity. These N-cadherin contacts are lost in mouse brain aging, and thereby may contribute to age-related BBB breakdown. However, the role of N-cadherin in regulating the BBB remains unknown. We invested the function of N-cadherin signaling in supporting the BBB using genetic mouse models and determined the underlying molecular mechanism by which N-cadherin restricts the BBB. We show that N-cadherin outside-in signaling induces a phosphoinositide 3-kinase (PI3K) β - Akt3 signaling axis to stabilize tight junctions by reducing the rate of internalization of occludin. My findings demonstrate a functional role of the N-cadherin adhesion complex to serve as a signaling hub to support the BBB.