Scientists Have Identified a Key Driver of Age-Related Cognitive Decline

A newly identified protein pathway may link blood-brain barrier deterioration to age-related cognitive decline. The aging brain depends on a microscopic border that works every second to keep danger out and support the nerve cells inside. When that barrier begins to fail, memory, mood, and thinking may suffer. Andrew A. Pieper, MD, PhD, and colleagues [...]

A newly identified protein pathway may link blood-brain barrier deterioration to age-related cognitive decline. The aging brain depends on a microscopic border that works every second to keep danger out and support the nerve cells inside. When that barrier begins to fail, memory, mood, and thinking may suffer.

Andrew A. Pieper, MD, PhD, and colleagues have now traced part of that breakdown to a single protein that appears to help keep the brain’s protective walls intact. The research, led by the Pieper Laboratory and published in Proceedings of the National Academy of Sciences, was conducted by a research group from University Hospitals, Case Western Reserve University and the Louis Stokes Cleveland VA Medical Center. The focus is the blood-brain barrier (BBB), a protective structure made from tightly packed endothelial cells that line the brain’s blood vessels.

Endothelial cells act like a living seal between the bloodstream and the brain. Maintaining that seal takes energy, but it allows the barrier to block harmful substances and pathogens, clear some waste produced during normal brain activity, and adjust blood flow toward whichever brain regions are working hardest. Scientists have known for years that these blood-brain barrier functions weaken in the aging brain.

However, whether that decline could directly drive cognitive problems, and what molecular change might be setting the process in motion, had remained uncertain. Without that missing cause, designing targeted treatments has been difficult. KLF4 emerges as a culprit “At the center of our findings is a protein called KLF4, which is produced by the endothelial cells that line the blood-brain barrier.

As people age, endothelial cells lose their ability to generate KLF4. We found that accelerating the loss of KLF4 in endothelial cells also accelerated aging-related BBB degradation and cognitive decline,” said Andrew A. Pieper, MD, PhD, senior