Summary: A new study explains why the blood-brain barrier — the brain’s protective lining — becomes more permeable with age and how that change can contribute to early memory decline. Researchers found that levels of two critical proteins, N-cadherin and occludin, fall over time, weakening the tight junctions that normally seal brain blood vessels. These changes begin by middle age, pointing to a sizable window for interventions to preserve cognitive function.
As N-cadherin and occludin diminish, the barrier becomes leakier and allows potentially harmful molecules to cross into the brain, disrupting neuronal activity and memory. The study identifies molecular pathways linking N-cadherin signaling to occludin stabilization and highlights possible therapeutic targets to slow or prevent age-related cognitive decline.
Key Facts:
- Protein Link: Aging reduces levels of N-cadherin and occludin, compromising blood-brain barrier integrity.
- Memory Impact: Loss of barrier function contributes to early cognitive and memory deficits.
- Therapeutic Potential: Restoring N-cadherin–dependent signaling could help stabilize occludin and repair the barrier.
Source: University of Illinois
Overview
Researchers at the University of Illinois Chicago have mapped a molecular route that links age-related changes in the blood-brain barrier (BBB) to memory loss. Published in Cell Reports, the study reveals how reduced N-cadherin signaling destabilizes occludin at tight junctions, increasing BBB permeability and impairing spatial memory in mice. Parallel observations in human brain tissue suggest the mechanism is relevant to people and begins in middle age, creating an opportunity for therapeutic intervention before substantial cognitive decline occurs.
The blood-brain barrier is a selective layer of endothelial cells that lines cerebral blood vessels and protects neural tissue from pathogens, toxins and unwanted proteins while permitting necessary nutrients and signaling molecules to pass. Tight junctions between endothelial cells form the BBB’s critical seal. Occludin is an essential tight-junction protein that contributes to this seal, and its stability determines how restrictive the barrier remains.
“The BBB is a dynamic, regulatable interface that selectively allows some molecules through while keeping others out,” said Yulia Komarova, associate professor in the UIC Department of Pharmacology and Regenerative Medicine and senior author of the study. “It effectively separates the central nervous system from the rest of the body, and when it fails, cognitive processes can be affected.”
Prior work from Komarova’s lab showed that deleting N-cadherin from vascular endothelial cells made blood vessels leakier in multiple organs, including the brain. In the current study, Komarova and co-author Leon Tai tested whether loss of N-cadherin affected learning and memory. Mice lacking functional N-cadherin learned tasks comparably to controls but showed rapid forgetting, indicating an impairment in memory retention rather than acquisition.
Detailed analyses revealed that both naturally aging brains and young mice with endothelial N-cadherin deletion had fewer occludin-containing tight junctions, producing a leakier barrier. Molecular experiments established that N-cadherin homophilic interactions between neighboring endothelial cells trigger a signaling cascade involving PI3K p110β and Akt3. This pathway promotes phosphorylation-dependent stabilization of occludin at tight junctions, preserving BBB integrity. When this signaling is disrupted, occludin is destabilized and tight junctions break down.
To confirm relevance to humans, Komarova collaborated with Dr. Jeffrey Loeb and examined cortical tissue from the university’s NeuroRepository collected during epilepsy surgeries. Comparing younger patients (late teens to twenties) with middle-aged patients (40s to 50s), the team observed reduced N-cadherin and occludin in the older samples, mirroring the mouse findings and supporting a conserved, age-related decline in this signaling axis.
Mechanistic experiments further showed that a specific occludin phosphorylation site (Ser471) is crucial: mutating this site to alanine destabilized occludin junctions even when N-cadherin contacts remained intact. This result underscores a phosphorylation-dependent mechanism by which N-cadherin–activated signaling maintains BBB tight junctions.
Because measurable declines in N-cadherin and occludin appear by middle age, the authors emphasize that there may be a substantial therapeutic window to intervene and protect cognitive function long before irreversible decline. The team is now exploring whether components of the N-cadherin–PI3K–Akt3 pathway can be targeted to restore occludin stability and BBB function.
Other UIC co-authors include Quinn Lee, Wang Ching Chan, Shuangping Zhao, Harry Hailemeskel, Riya Thomas, Mohsin Zafar, Fozia Mir, Peter Toth and Kamran Avanki.
About this aging and neurology research news
Author: Francesca Sacco
Source: University of Illinois
Contact: Francesca Sacco – University of Illinois
Image: The image is credited to Neuroscience News
Original Research: Open access. “Deficiency in N-cadherin-Akt3 signaling impairs the blood-brain barrier” by Yulia Komarova et al., Cell Reports (full study available as an open-access article).
Abstract
Deficiency in N-cadherin-Akt3 signaling impairs the blood-brain barrier
The blood-brain barrier (BBB) limits passage of protein-rich fluids across tight junctions (TJs) formed between brain endothelial cells (BECs). Restrictiveness of the BBB declines with age, but the mechanisms have been unclear. BECs form physical contacts with pericytes through N-cadherin homophilic adhesion. In cortical tissue from young and middle-aged individuals, age-related loss of vascular N-cadherin correlates with disruption of occludin-containing TJs. Genetic deletion of N-cadherin in endothelial cells impairs occludin TJs, reduces cerebral tissue perfusion and leads to spatial memory deficits. Mechanistically, assembly of N-cadherin contacts stabilizes occludin TJs through a phosphoinositide 3-kinase p110β–Akt3 signaling circuit that is disrupted with aging. Mutation of occludin Ser471 to Ala destabilizes occludin TJs even when N-cadherin contacts are present. These findings position N-cadherin as a signaling hub that stabilizes occludin via phosphorylation-dependent mechanisms, thereby supporting BBB integrity and cognitive health.