Description
- Abstract:
- Background: As we get older, various aspects of our bodies start to decline, including brain function. The mechanisms behind the decline in brain function due to aging are still not well understood. The blood-brain barrier (BBB) is crucial for maintaining brain health and homeostasis across the lifespan by controlling both passive and active exchange of materials between the blood and brain, as well as neurovascular coupling, which is instantly calibrates delivery of blood to brain regions to precisely match their energy demand. Both aging and neurodegenerative disorders are associated with deterioration of endothelial cells, the primary component of the BBB. Endothelial cells are highly enriched in the Kruppel-like factor 4 (KLF4) transcription factor, which is also reduced in expression with aging. Study Design and Methodology: Through neurobehavioral tests, two-photon microscopy, histological analysis, and single-cell RNA sequencing, we compared the brain health of endothelial-specific KLF4 knockout (EC-K4KO) mice compared to wild-type littermates across the lifespan. Results: We observed that EC-K4KO mice display accelerated brain aging, including accelerated BBB deterioration, neurodegeneration, neuroinflammation, and cognitive decline. Single-cell RNA sequencing from brain endothelial cells of EC-K4KO mice revealed aberrantly high expression of adaptive and innate immune response genes. In addition, live animal brain imaging across the lifespan revealed accelerated BBB leakage, decreased blood flow, and impaired neurovascular coupling. Conclusion: We show that the specific loss of KLF4 from endothelial cells promotes breakdown of the blood-brain barrier (BBB), a key aspect of brain aging, which is associated with vascular and neuronal pathology leading to cognitive decline. EC-K4KO mice provide a model of microvascular dysfunction in aging that was previously lacking in the field of brain health. Endothelial KLF4 or its downstream pathways could offer a novel strategy to protect the health and function of the aging brain.
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Citation
Indrakumar, Vidya , Vázquez-Rosa, Edwin , Dhar, Matasha , Liao, Xudong , Chakraborty, Suwarna , Tripathi, Sunil Jamuna , Fang, Hua , Shin, Min-Kyoo , Koh, Yeojung , Miller, Emiko , Tang, Xinmiao , Sridharan, Preethy , Chaubey, Kalyani , Franke, Kathryn , Corella, Sofia , Cintrón-Pérez, Adrian , Rubin, Phoebe J. , Ashiku, Luke , Pieper, Justin , Tomco, Taylor , Cintrón-Pérez, Coral , Padmanabhan, Roshan , Haragopal, Hariprakash , Flanagan, Margaret E. , Jain, Rajan , Winters, Bradley D. , Wilson, Brigid M. , Paul, Bindu D. , Jain, Mukesh K. , Pieper, Andrew A.,
"Depletion of Endothelial Krüppel-like Factor 4 (KLF4) Drives Age-Related Neurovascular Dysfunction and Neuropsychiatric Impairment"
(2025).
Student Neurosurgery/Neurology Research Conference.
Brown Digital Repository. Brown University Library.
https://doi.org/10.26300/hd4r-qx13
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Student Neurosurgery/Neurology Research Conference
Brown University Department of Neurosurgery and Department of Neurology and Warren Alpert Medical School annually hosts the Student Neurosurgery/Neurology Research Conference, a national conference for medical students conducting research in neurosurgery/neurology or related neuroscience fields....