Molecular cause of age-related cognitive decline has been identified

A key role in the process is played by the KLF4 protein, which is produced by the endothelial cells of the BBB. With age, the ability of cells to produce KLF4 decreases. Scientists have found that if you artificially accelerate the loss of KLF4 in endothelial cells, then the degradation of the BBB and cognitive impairment occur faster.

To trace the changes, the team used two-photon microscopy and observed the activity of the brain and blood vessels in live mice at different stages of life. It turned out that KLF4 deficiency leads to a leaky BBB, a reduction in the number of small blood vessels in the brain, and a disruption in the connection between blood flow and neuronal activity.

In middle-aged mice, these changes caused oxidative damage to the brain, neuroinflammation, neuronal death, anxiety, and cognitive decline, conditions that are typically observed only in much older animals.

Additional analysis using single-cell RNA sequencing revealed that the loss of KLF4 disrupts the functioning of gene programs related to the immune response and BBB integrity. This helps explain why the protein is so important for brain health.

According to the study’s senior author, Dr. Andrew A. Piper, the findings suggest a promising avenue for the development of neuroprotective drugs. A therapy that preserves or restores KLF4 function in endothelial cells could slow down the age-related degradation of the blood-brain barrier and the associated decline in cognitive abilities.

The next step is to identify the reasons why KLF4 levels decrease with age and find safe ways to increase its activity to protect the brain. This discovery provides an important starting point for the development of new medications aimed at maintaining brain health in old age.