Cleveland Research Team Identifies Key Driver of Age-Related Cognitive Decline

Researchers from University Hospitals, Case Western Reserve University and the Cleveland VA published preclinical results in Proceedings of the National Academy of Sciences (PNAS)

• Researchers at University Hospitals, Case Western Reserve University and the Cleveland VA identified a key molecular driver of age-related cognitive decline, offering a potential path toward the development of new treatments.
• Published today in PNAS, the study pinpoints a key protein behind age-related breakdown of the blood-brain barrier (BBB), which leads to cognitive decline.
• The research team showed that loss of a protein called KLF4 in blood vessel cells weakens the BBB and accelerates brain aging.
• In preclinical models, this loss impaired BBB function and proper coupling of blood supply with neuronal activity, which triggered neurodegeneration, inflammation and cognitive decline - changes typically seen only in much older individuals.
• The findings point to KLF4 as a promising therapeutic target, with future treatments potentially aimed at preserving or restoring its function to protect the aging brain.

CLEVELAND - A research team from University Hospitals, Case Western Reserve University and the Louis Stokes Cleveland VA Medical Center has identified a critical molecular cause of age-related cognitive decline, potentially paving the way for new treatments to protect brain health as we age.

Their research, led by the Pieper Laboratory, published today in Proceedings of the National Academy of Sciences.

The study centers on a protective structure called the blood-brain barrier (BBB). Within this structure, the endothelial cells lining the blood vessels are tightly packed through an energetically demanding process that keeps harmful substances and pathogens in the bloodstream from entering the brain, removes some waste products that accumulate during normal brain activity, and dynamically adjusts blood flow to whichever areas of the brain are most active at any given moment.

Breakdown of these critical functions of the BBB has long been observed in the aging brain, but whether this is sufficient to cause cognitive decline in aging has not been previously established. Furthermore, the underlying molecular causes of aging-related BBB degradation have remained unclear, limiting the development of targeted treatments.

"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 author of the study, University Hospitals Morley-Mather Chair of Neuropsychiatry, and Rebecca E. Barchas, MD, DLFAPA, Case Western Reserve University Professor of Translational Psychiatry."

Using advanced two-photon microscopy to monitor brain and blood vessel activity in living mice at multiple points across their lifespan, the team observed that loss of KLF4 caused the BBB to leak, reduced the abundance of small blood vessels in the brain, and disrupted the BBB's ability to match blood supply to neuronal activity. Even in middle-aged mice, these changes triggered oxidative brain damage, neuroinflammation, nerve cell damage, anxiety, and cognitive decline, conditions normally seen only in much older animals.

"Loss of endothelial cell KLF4 accelerated every key aspect of brain aging that we measured. This suggests that therapies designed to preserve or restore KLF4 function in endothelial cells may help prevent age-related deterioration of the blood-brain barrier and the cognitive decline that follows," added Dr. Pieper, who also serves as director of the Brain Health Medicines Center at Harrington Discovery Institute at UH, and psychiatrist and investigator in the Louis Stokes VA Geriatric Research Education and Clinical Center.

Further analysis using single-cell RNA sequencing showed that loss of KLF4 disrupted gene programs tied to immune response and BBB integrity, helping explain its central role in maintaining brain health.

The identification of a major culprit in age-related cognitive decline has opened important new lines of investigation required for developing neuroprotective therapeutics. Next steps in this research involve utilizing the findings to open new avenues for future studies and drug development focused on why KLF4 declines with age and how its activity can be safely enhanced to protect the brain.

###

This work was the result of a close collaboration between two physician-scientists at the Harrington Discovery Institute: cardiologist Mukesh Jain, MD, (now Dean at Brown University); with expertise in KLF4 and vascular biology, and psychiatrist-neuroscientist Andrew A. Pieper, MD, PhD, with expertise in brain health and neurodegenerative disease.

Finding answers to complex problems that are currently unsolved in medicine today requires this type of interdisciplinary collaboration supported in Cleveland at Harrington Discovery Institute at UH, University Hospitals, Case Western Reserve University and the Louis Stokes VA Medical Center.

M. Dhar, M.K. Jain, & A.A. Pieper, et al. Endothelial KLF4 depletion drives age-related neurovascular dysfunction and neuropsychiatric impairment, Proc. Natl. Acad. Sci. U.S.A. 123 (25) e2426990123, https://www.pnas.org/doi/10.1073/pnas.2426990123