A research team from University Hospitals, Case Western Reserve University, and the Louis Stokes Cleveland VA Medical Center has identified a key molecular driver of age-related cognitive decline. This discovery could lead to new treatments to preserve brain health in older adults. The findings, led by the Pieper Laboratory and published in the Proceedings of the National Academy of Sciences, point to a protein called KLF4 as a critical factor in maintaining the health of the blood-brain barrier (BBB). This protective network shields the brain from harmful substances while supporting normal brain function.
The blood-brain barrier is formed by tightly connected endothelial cells that line blood vessels in the brain. These cells regulate which molecules enter the brain, remove certain waste products generated by normal brain activity, and ensure blood flow is directed to the areas of the brain that need it most. Although deterioration of the BBB has long been associated with ageing, scientists had not established whether this breakdown directly contributes to cognitive decline or identified the molecular mechanisms responsible for its deterioration.
The researchers found that ageing endothelial cells gradually lose their ability to produce KLF4, a protein essential for maintaining the integrity of the blood-brain barrier. To investigate its role, the team reduced KLF4 levels in the endothelial cells of mice and monitored changes using advanced two-photon microscopy throughout the animals’ lifespan. Mice with accelerated KLF4 loss developed leaky blood vessels, fewer small blood vessels in the brain, and impaired regulation of blood flow in response to neuronal activity.
These vascular changes had widespread consequences. Even in middle-aged mice, reduced KLF4 triggered oxidative damage, neuroinflammation, nerve cell injury, anxiety-like behaviours, and measurable cognitive decline—changes typically seen only in much older animals. According to senior author Dr. Andrew A. Pieper, the loss of endothelial cell KLF4 accelerated every major feature of brain ageing examined in the study, suggesting that preserving KLF4 function could help protect the brain from age-related deterioration.
The team also used single-cell RNA sequencing to understand the underlying biology better. Their analysis showed that KLF4 loss disrupted multiple gene programmes involved in maintaining the blood-brain barrier and regulating immune responses, providing further evidence that the protein plays a central role in preserving brain health. These findings help explain how declining KLF4 levels contribute to the progressive breakdown of the BBB during ageing.
The discovery identifies KLF4 as a promising therapeutic target for slowing or preventing age-related cognitive decline. Future research will focus on understanding why KLF4 levels decrease with age and whether drugs can safely restore or enhance its activity in endothelial cells. If successful, such treatments could help maintain the integrity of the blood-brain barrier, protect the ageing brain, and reduce the risk of cognitive impairment later in life.
More information: Matasha Dhar et al, Endothelial KLF4 depletion drives age-related neurovascular dysfunction and neuropsychiatric impairment, Proceedings of the National Academy of Science. DOI: 10.1073/pnas.2426990123
Journal information: Proceedings of the National Academy of Science Provided by University Hospitals Cleveland Medical Center
