Endothelial KLF4 depletion drives age-related neurovascular dysfunction and neuropsychiatric impairment
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (32)
Matasha Dhar
Department of Psychiatry, School of Medicine, Case Western Reserve University
Edwin Vázquez-Rosa
Department of Psychiatry, Case Western Reserve University
Kalyani Chaubey
Department of Psychiatry, Case Western Reserve University
Emiko Miller
Department of Psychiatry, Case Western Reserve University
Sofia G. Corella
Department of Psychiatry, Case Western Reserve University
Suwarna Chakraborty
Department of Physiology, Pharmacology, & Therapeutics, Johns Hopkins University School of Medicine
Sunil Jamuna Tripathi
Department of Physiology, Pharmacology, & Therapeutics, Johns Hopkins University School of Medicine
Tapatee Das
Department of Molecular Biology, Cell Biology and Biochemistry, Division of Biology and Medicine, Brown University
Xudong Liao
Department of Molecular Biology, Cell Biology and Biochemistry, Division of Biology and Medicine, Brown University
Mohamed Alkassem Alosman
Department of Molecular Biology, Cell Biology and Biochemistry, Division of Biology and Medicine, Brown University
Hua Fang
Discovery and Development Sciences
Yeojung Koh
Department of Psychiatry, School of Medicine, Case Western Reserve University
Preethy S. Sridharan
Department of Psychiatry, School of Medicine, Case Western Reserve University
Kathryn Franke
Department of Psychiatry, School of Medicine, Case Western Reserve University
Coral J. Cintrón-Pérez
Department of Psychiatry, School of Medicine, Case Western Reserve University
Adrian A. Cintrón-Pérez
Department of Psychiatry, Case Western Reserve University
Taylor Tomco
Department of Psychiatry, Case Western Reserve University
Vidya Indrakumar
Department of Psychiatry, School of Medicine, Case Western Reserve University
Phoebe J. Rubin
Department of Psychiatry, Case Western Reserve University
Justin G. Pieper
Department of Psychiatry, Case Western Reserve University
Luke A. Ashiku
Department of Psychiatry, Case Western Reserve University
Min-Kyoo Shin
Department of Psychiatry, School of Medicine, Case Western Reserve University
Xinmiao Tang
Yueyang Hospital, Shanghai University of Traditional Chinese Medicine
Roshan Padmanabhan
Trailhead Biosystems Inc.
Hariprakash Haragopal
Department of Biomedical Sciences, Northeast Ohio Medical University
Margaret E. Flanagan
Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Feinberg School of Medicine, Northwestern University
Rajan Jain
Departments of Medicine and Cell and Developmental Biology, Penn Cardiovascular Institute, Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania
Bradley D. Winters
Department of Biomedical Sciences, Northeast Ohio Medical University
Brigid M. Wilson
Geriatric Psychiatry, Geriatric Research Education and Clinical Center, Louis Stokes VA Medical Center
Bindu D. Paul
Department of Physiology, Pharmacology, & Therapeutics, Johns Hopkins University School of Medicine
Mukesh K. Jain
Department of Molecular Biology, Cell Biology and Biochemistry, The Warren Alpert Medical School, Brown University
Andrew A. Pieper
Department of Psychiatry, Case Western Reserve University