Endothelial KLF4 depletion drives age-related neurovascular dysfunction and neuropsychiatric impairment

Deterioration of the blood–brain barrier (BBB), including impaired neurovascular uncoupling, contributes to cognitive decline in aging. The BBB is formed principally by brain microvascular endothelial cells (ECs), and ECs throughout the body are enriched for the transcription factor Krüppel-like factor 4 (KLF4). Because KLF4 levels in ECs decrease with age, we tested whether that decline contributes to aging-related BBB deterioration, neurovascular dysfunction, and cognitive impairment. Using EC-specific Klf4 knockout mice (EC-K4KO), we show that loss of EC KLF4 accelerates multiple age-related brain pathologies. Indeed, middle-aged EC-K4KO mice display pathological features that are not normally observed until advanced age, including marked BBB leakage, impaired neurovascular coupling, loss of microvessels, increased oxidative damage, neuroinflammation, neurodegeneration, anxiety-like behavior, and cognitive deficits. Single-cell RNA sequencing of brain vasculature reveals dysregulation of immune response and barrier-related genes in ECs lacking KLF4, indicating that KLF4 maintains brain endothelial homeostasis by constraining proinflammatory and senescence programs at the chromatin level. Together, these results identify loss of EC KLF4 as a key driver of neurovascular decline and age-associated cognitive dysfunction.

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Journal
Proceedings of the National Academy of Sciences
Published
2026-06-18
DOI
https://doi.org/10.1073/pnas.2426990123
Primary Topic
Kruppel-like factors research
Type
article
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article

Endothelial KLF4 depletion drives age-related neurovascular dysfunction and neuropsychiatric impairment

Kathryn Franke, Mukesh K. Jain, Bindu D. Paul, Bradley D. Winters et al.
Proceedings of the National Academy of Sciences
Kruppel-like factors research
article

Endothelial KLF4 depletion drives age-related neurovascular dysfunction and neuropsychiatric impairment

Kathryn Franke, Mukesh K. Jain, Bindu D. Paul, Bradley D. Winters, Rajan Jain, Kalyani Chaubey, Emiko Miller, Preethy S. Sridharan, Yeojung Koh, Xinmiao Tang, Sunil Jamuna Tripathi, Hariprakash Haragopal, Xudong Liao, Andrew A. Pieper, Suwarna Chakraborty, Brigid Wilson, Matasha Dhar, Tapatee Das, Coral J. Cintrón-Pérez, Edwin Vázquez‐Rosa, Sofia Corella, Min-Kyoo Shin, Roshan Padmanabhan, Taylor Tomco, Vidya Indrakumar, Mohamed Alkassem Alosman, Adrian A. Cintrón-Pérez, Margaret E. Flanagan, Hua Fang, Luke A. Ashiku, Phoebe J. Rubin, Justin G. Pieper
article en

Abstract

Deterioration of the blood–brain barrier (BBB), including impaired neurovascular uncoupling, contributes to cognitive decline in aging. The BBB is formed principally by brain microvascular endothelial cells (ECs), and ECs throughout the body are enriched for the transcription factor Krüppel-like factor 4 (KLF4). Because KLF4 levels in ECs decrease with age, we tested whether that decline contributes to aging-related BBB deterioration, neurovascular dysfunction, and cognitive impairment. Using EC-specific Klf4 knockout mice (EC-K4KO), we show that loss of EC KLF4 accelerates multiple age-related brain pathologies. Indeed, middle-aged EC-K4KO mice display pathological features that are not normally observed until advanced age, including marked BBB leakage, impaired neurovascular coupling, loss of microvessels, increased oxidative damage, neuroinflammation, neurodegeneration, anxiety-like behavior, and cognitive deficits. Single-cell RNA sequencing of brain vasculature reveals dysregulation of immune response and barrier-related genes in ECs lacking KLF4, indicating that KLF4 maintains brain endothelial homeostasis by constraining proinflammatory and senescence programs at the chromatin level. Together, these results identify loss of EC KLF4 as a key driver of neurovascular decline and age-associated cognitive dysfunction.

Proceedings of the National Academy of SciencesVol. 123(25)
Cato Institute (US), Seoul National University (KR), Johns Hopkins University (US), The University of Texas at San Antonio Health Science Center (US), John Brown University (US), Brown University (US), Discovery Institute (US), Johns Hopkins Medicine (US), University of California System (US), Arrowhead Pharmaceuticals (United States) (US), Shanghai University of Traditional Chinese Medicine (CN), University Hospitals Cleveland Medical Center (US), Geriatric Research Education and Clinical Center (US), Institute for Neurodegenerative Disorders (US), Yueyang Hospital (CN), Lieber Institute for Brain Development (US), Case Western Reserve University (US), Massachusetts Institute of Technology (US), University of Pennsylvania (US), Universidad del Noreste (MX), The University of Texas Health Science Center at Houston (US), Northeast Ohio Medical University (US)
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