Study Reveals How Blood-Brain Barrier Leakiness Increases with Age

Researchers at the University of Illinois Chicago have revealed how the blood-brain barrier (BBB) becomes more permeable with age, potentially leading to memory deficits. Their study, published in Cell Reports, provides insights into the molecular mechanisms driving this age-related change and suggests possible therapeutic targets to counteract cognitive decline during aging.

The BBB is a critical protective layer formed by cells lining the brain’s blood vessels. Its role is to block harmful substances such as viruses, bacteria, and toxins from entering the brain while allowing essential nutrients and chemicals to pass through. This selective permeability depends largely on tight junctions—protein structures that create bridges between endothelial cells. The protein occludin is a key component of these tight junctions, helping maintain the barrier’s integrity.

"It is a highly regulatable process that allows some molecules to go through and others to remain in circulation," explained Yulia Komarova, senior author of the study. However, with age, the barrier’s function deteriorates and it becomes leaky, which can contribute to memory changes starting as early as middle age.

Previous studies from Komarova’s group showed that deleting N-cadherin, a protein expressed on blood vessel cells, caused leakiness in both lung and brain vessels. In this new study, the researchers investigated how loss of N-cadherin affected memory. They found that mice lacking functional N-cadherin performed normally when learning new tasks but rapidly forgot them, linking memory issues to barrier dysfunction.

Closer examination showed that both aged brains and brains without N-cadherin had reduced occludin in tight junctions, weakening the BBB. The team discovered that when N-cadherin proteins on neighboring cells interact, they activate a signaling pathway that stabilizes occludin and preserves tight junctions, supporting BBB integrity.

Human brain tissue analysis from epilepsy surgery samples corroborated these findings. Middle-aged adults (40s to 50s) showed decreased levels of both N-cadherin and occludin compared to younger individuals (late teens to 20s), mirroring the mouse data. 

Because these changes appear in middle age, Komarova emphasized, "it’s not too late in the game to start treatment." Her team is now exploring if components of the N-cadherin signaling pathway could serve as therapeutic targets to slow or prevent cognitive decline.

“This paper shows that actually there might be a much bigger therapeutic window for treatment of any age-related cognitive decline condition,” she added.