Inhibiting 15-PGDH blocks blood–brain barrier deterioration and protects mice from Alzheimer’s disease and traumatic brain injury
Abstract
Alzheimer’s disease (AD) and traumatic brain injury (TBI) are currently untreatable neurodegenerative disorders afflicting millions of people worldwide. These conditions are pathologically related, and TBI is one of the greatest risk factors for AD. Although blood–brain barrier (BBB) disruption drives progression of both AD and TBI, strategies to preserve BBB integrity have been hindered by lack of actionable targets. Here, we identify 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that catabolizes eicosanoids and other anti-inflammatory mediators, as a therapeutic candidate that protects the BBB. We demonstrate that 15-PGDH is enriched in BBB-associated myeloid cells and becomes markedly elevated in human and mouse models of AD and TBI, as well as aging, another major risk factor for AD. Pathological increase in 15-PGDH correlates with pronounced oxidative stress, neuroinflammation, and neurodegeneration, alongside profound BBB structural degeneration characterized by astrocytic endfeet swelling and functional impairment. Pharmacologic inhibition or genetic reduction of 15-PGDH in AD and TBI models strikingly mitigates oxidative damage, suppresses neuroinflammation, and restores BBB integrity. Most notably, inhibiting 15-PGDH not only halts neurodegeneration but also preserves cognitive function at levels indistinguishable from healthy controls. Remarkably, these neuroprotective effects in AD are achieved without affecting amyloid pathology, underscoring a noncanonical mechanism for treating AD. In a murine microglia cell line exposed to amyloid beta oligomer, major protection was demonstrated by multiple anti-inflammatory substrates that 15-PGDH degrades. Thus, our findings position 15-PGDH inhibition as a broad-spectrum strategy to protect the BBB and thereby preserve brain health and cognition in AD and TBI.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (49)
Yeojung Koh
Department of Psychiatry, School of Medicine, Case Western Reserve University
Edwin Vázquez-Rosa
Department of Psychiatry, Case Western Reserve University
Farrah Gao
Department of Genetics and Genome Sciences School of Medicine, Case Western Reserve University
Hongyun Li
Case Comprehensive Cancer Center, 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
Sarah Barker
Department of Psychiatry, School of Medicine, Case Western Reserve University
Zea Bud
Department of Psychiatry, School of Medicine, Case Western Reserve University
Anusha Bangalore
Department of Psychiatry, School of Medicine, Case Western Reserve University
Uapingena P. Kandjoze
Department of Psychiatry, School of Medicine, Case Western Reserve University
Rose A León-Alvarado
Department of Psychiatry, School of Medicine, Case Western Reserve University
Preethy S. Sridharan
Department of Psychiatry, School of Medicine, Case Western Reserve University
Brittany A. Cordova
Case Comprehensive Cancer Center, Case Western Reserve University
Youngmin Yu
Department of Psychiatry, School of Medicine, Case Western Reserve University
Jiwon Hyung
Department of Psychiatry, School of Medicine, Case Western Reserve University
Hua Fang
Discovery and Development Sciences
Salendra Singh
Case Comprehensive Cancer Center, Case Western Reserve University
Ramachandra Katabathula
Case Comprehensive Cancer Center, Case Western Reserve University
Thomas LaFramboise
Department of Genetics and Genome Sciences School of Medicine, Case Western Reserve University
Lakshmi Kasturi
Department of Medicine, School of Medicine Case Western Reserve University
James Lutterbaugh
Department of Medicine, School of Medicine Case Western Reserve University
Lydia Beard
Department of Medicine, School of Medicine Case Western Reserve University
Erika Cordova
Department of Medicine, School of Medicine Case Western Reserve University
Coral J. Cintrón-Pérez
Department of Psychiatry, School of Medicine, Case Western Reserve University
Kathryn Franke
Department of Psychiatry, School of Medicine, Case Western Reserve University
Mariana Franco Fragoso
Case Comprehensive Cancer Center, Case Western Reserve University
Emiko Miller
Department of Psychiatry, Case Western Reserve University
Vidya Indrakumar
Department of Psychiatry, School of Medicine, Case Western Reserve University
Kamryn L. Noel
Department of Psychiatry, School of Medicine, Case Western Reserve University
Matasha Dhar
Department of Psychiatry, School of Medicine, Case Western Reserve University
Kaouther Ajroud
Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Feinberg School of Medicine, Northwestern University
Carlos Zamudio
Department of Pathology, Northwestern University
Filipa Blasco Tavares Pereira Lopes
Department of Nutrition, School of Medicine, Case Western Reserve University
Evangeline Bambakidis
Department of Psychiatry, School of Medicine, Case Western Reserve University
Xiongwei Zhu
Department of Pathology, Case Western Reserve University
Brigid Wilson
Geriatric Psychiatry, Geriatric Research Education and Clinical Center, Louis Stokes Veterans Affairs Medical Center
Margaret E. Flanagan
Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Feinberg School of Medicine, Northwestern University
Tamar Gefen
Hisashi Fujioka
Cryo-Electron Microscopy Core Facility, Case Western Reserve University School of Medicine
Stephen P. Fink
Case Comprehensive Cancer Center, Case Western Reserve University
Amar B. Desai
Department of Pathology, School of Medicine Case Western Reserve University
Dawn Dawson
Department of Pathology, School of Medicine Case Western Reserve University
Noelle S. Williams
Department of Biochemistry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390, United States
Young-Kwang Kim
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University
Joseph M. Ready
Bindu D. Paul
Department of Physiology, Pharmacology, & Therapeutics, Johns Hopkins University School of Medicine
Min-Kyoo Shin
Department of Psychiatry, School of Medicine, Case Western Reserve University
Sanford D. Markowitz
Case Comprehensive Cancer Center, Case Western Reserve University
Andrew A. Pieper
Department of Psychiatry, Case Western Reserve University