Aging leads to the deterioration of the Blood-Brain Barrier.
In a groundbreaking study published in the journal Cell Reports, a team of researchers led by Yulia Komarova from the University of Illinois have shed light on the crucial role of the protein N-cadherin in maintaining the integrity of the blood-brain barrier (BBB).
The BBB, a barrier formed by tight junctions between endothelial cells lining brain blood vessels, plays a vital role in preserving brain homeostasis and cognitive function. It restricts the passage of protein-rich fluids while allowing essential nutrients to pass, thereby protecting the brain from harmful substances.
N-cadherin, expressed on neighbouring blood vessel cells, triggers a signalling pathway that stabilizes occludin, a key tight junction protein. The interaction between N-cadherin molecules reinforces the organization and function of occludin, thus maintaining BBB integrity.
Aging is associated with a decrease in both N-cadherin and occludin levels, leading to weakening of these tight junctions and making the BBB more "leaky." This leakiness permits entry of toxins and pathogens that can damage brain tissue, contributing to cognitive decline observed even from middle age onward.
Moreover, breakdown of occludin can occur pathologically via proteolytic cleavage by enzymes such as BACE1, which is elevated under some conditions (e.g., hypertension, inflammation). This cleavage further disrupts tight junctions and impairs BBB function, exacerbating neurovascular and cognitive dysfunction.
The study found that N-cadherin acts as a stabilizing signal for occludin-based tight junctions, and loss of these proteins with aging compromises the BBB. This contributes to cognitive decline by allowing harmful substances into the brain.
The findings highlight a functional role for N-cadherin as a signaling hub that stabilizes occludin at tight junctions in a phosphorylation-dependent manner, thereby supporting BBB integrity. The study is the first to investigate how N-cadherin signalling controls the organization of tight junctions implicated in blood-brain barrier permeability.
The research suggests that there might be a larger therapeutic window for treating age-related cognitive decline conditions. By targeting the N-cadherin signalling pathway or related mechanisms, it may be possible to help preserve BBB integrity and cognitive health during aging.
The study was conducted by a team including Quinn Lee, Wang Ching Chan, Shuangping Zhao, Harry Hailemeskel, Riya Thomas, Mohsin Zafar, Fozia Mir, Peter Toth, and Kamran Avanki from the University of Illinois.
As we age, the BBB's restrictiveness diminishes, and the underlying mechanisms are unclear. This study provides valuable insights into the molecular changes that occur with aging and their impact on BBB function and cognitive health.
- The protein N-cadherin, discovered in a groundbreaking study, is crucial for maintaining the integrity of the blood-brain barrier (BBB), which is important for preserving brain homeostasis and cognitive function.
- Aging is associated with a decrease in N-cadherin and occludin levels, leading to weakening of the tight junctions that make up the BBB, making it more "leaky" and permitting entry of harmful substances.
- These harmful substances can damage brain tissue, contributing to cognitive decline that may be observed even from middle age onward.
- The study reveals that N-cadherin acts as a stabilizing signal for occludin-based tight junctions, and its loss with aging compromises the BBB, ultimately leading to cognitive decline.
- The findings suggest a potential therapeutic approach for aging-related cognitive decline conditions, as targeting the N-cadherin signaling pathway or related mechanisms may help preserve BBB integrity and cognitive health during aging.
- The research was conducted by a team from the University of Illinois, providing valuable insights into the molecular changes that occur with aging and their impact on BBB function and mental health.
