Molecular Insights into Age-Related Increase in Blood-Brain Barrier Leakiness

Recent research from the University of Illinois Chicago sheds light on how the blood-brain barrier (BBB) becomes more permeable with age, potentially leading to early memory impairments. Published in Cell Reports, the study uncovers the molecular mechanisms responsible for this decline, offering new avenues for therapeutic intervention.

The BBB is a protective layer of cells lining brain blood vessels, crucial in maintaining neural environment stability by blocking harmful substances like bacteria and toxins from entering the brain. Central to this function are tight junctions—protein structures that connect endothelial cells—facilitated by proteins such as occludin. The process is highly regulated, allowing selective passage of beneficial molecules while maintaining a defensive barrier.

As we age, however, the integrity of the BBB diminishes, resulting in increased leakiness. This deterioration is linked to a reduction in proteins like N-cadherin and occludin, which destabilize tight junctions. Previous studies led by Yulia Komarova demonstrated that removing N-cadherin from blood vessel cells caused the vessels to become more permeable in both lungs and brain.

In the current study, researchers observed that mice lacking functional N-cadherin showed impaired memory, despite normal learning capabilities. Examination of these mice's brains revealed fewer occludin-containing tight junctions, correlating with increased barrier permeability. Molecular experiments identified that N-cadherin interactions activate signaling pathways that stabilize occludin, thus maintaining BBB integrity.

The team also analyzed human brain tissue from epilepsy surgeries, comparing younger and middle-aged individuals. Results indicated that older brains displayed decreased levels of N-cadherin and occludin, paralleling findings in the mouse model.

This research is pioneering in demonstrating how N-cadherin-dependent signaling controls the organization of tight junctions and influences BBB permeability. Since these changes occur relatively early—during middle age—they suggest that early intervention could potentially prevent or delay cognitive decline. The team is now exploring whether modulating this signaling pathway offers a promising therapeutic strategy.

Ultimately, this work highlights the possibility of a broader window for treating age-related cognitive impairments, emphasizing the importance of early detection and intervention to preserve brain health.