Inhibiting 15-PGDH blocks blood–brain barrier deterioration and protects mice from Alzheimer’s disease and traumatic brain injury Article Swipe
Yeojung Koh
,
Edwin Vázquez‐Rosa
,
Farrah Gao
,
Hongyun Li
,
Suwarna Chakraborty
,
Sunil Jamuna Tripathi
,
Sarah Barker
,
Zea Bud
,
Anusha Bangalore
,
Uapingena P. Kandjoze
,
Rose A León-Alvarado
,
Preethy Sridharan
,
Brittany A. Cordova
,
Youngmin Yu
,
Jaewon Hyung
,
Hua Fang
,
Salendra Singh
,
Ramachandra Katabathula
,
Thomas LaFramboise
,
Lakshmi Kasturi
,
James Lutterbaugh
,
Lydia Beard
,
Erika Cordova
,
Coral J. Cintrón-Pérez
,
Kathryn Franke
,
Mariana F. Fragoso
,
Emiko Miller
,
Vidya Indrakumar
,
Kamryn L. Noel
,
Matasha Dhar
,
Kaouther Ajroud
,
Carlos Zamudio
,
Filipa Blasco Tavares Pereira Lopes
,
Evangeline Bambakidis
,
Xiongwei Zhu
,
Brigid Wilson
,
Margaret E. Flanagan
,
Tamar Gefen
,
Hisashi Fujioka
,
Stephen P. Fink
,
Amar Desai
,
Dawn Dawson
,
Noelle S. Williams
,
Young-Kwang Kim
,
Joseph M. Ready
,
Bindu D. Paul
,
Min‐Kyoo Shin
,
Sanford D. Markowitz
,
Andrew A. Pieper
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1073/pnas.2417224122
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1073/pnas.2417224122
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.
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- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1073/pnas.2417224122
- https://www.pnas.org/doi/pdf/10.1073/pnas.2417224122
- OA Status
- hybrid
- Cited By
- 3
- References
- 79
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4410553407
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4410553407Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1073/pnas.2417224122Digital Object Identifier
- Title
-
Inhibiting 15-PGDH blocks blood–brain barrier deterioration and protects mice from Alzheimer’s disease and traumatic brain injuryWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2025Year of publication
- Publication date
-
2025-05-21Full publication date if available
- Authors
-
Yeojung Koh, Edwin Vázquez‐Rosa, Farrah Gao, Hongyun Li, Suwarna Chakraborty, Sunil Jamuna Tripathi, Sarah Barker, Zea Bud, Anusha Bangalore, Uapingena P. Kandjoze, Rose A León-Alvarado, Preethy Sridharan, Brittany A. Cordova, Youngmin Yu, Jaewon Hyung, Hua Fang, Salendra Singh, Ramachandra Katabathula, Thomas LaFramboise, Lakshmi Kasturi, James Lutterbaugh, Lydia Beard, Erika Cordova, Coral J. Cintrón-Pérez, Kathryn Franke, Mariana F. Fragoso, Emiko Miller, Vidya Indrakumar, Kamryn L. Noel, Matasha Dhar, Kaouther Ajroud, Carlos Zamudio, Filipa Blasco Tavares Pereira Lopes, Evangeline Bambakidis, Xiongwei Zhu, Brigid Wilson, Margaret E. Flanagan, Tamar Gefen, Hisashi Fujioka, Stephen P. Fink, Amar Desai, Dawn Dawson, Noelle S. Williams, Young-Kwang Kim, Joseph M. Ready, Bindu D. Paul, Min‐Kyoo Shin, Sanford D. Markowitz, Andrew A. PieperList of authors in order
- Landing page
-
https://doi.org/10.1073/pnas.2417224122Publisher landing page
- PDF URL
-
https://www.pnas.org/doi/pdf/10.1073/pnas.2417224122Direct link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
hybridOpen access status per OpenAlex
- OA URL
-
https://www.pnas.org/doi/pdf/10.1073/pnas.2417224122Direct OA link when available
- Concepts
-
Neuroinflammation, Neurodegeneration, Microglia, Traumatic brain injury, Neuroprotection, Oxidative stress, Blood–brain barrier, Proinflammatory cytokine, Inflammation, Medicine, Disease, Neuroscience, Amyloid beta, Biology, Pharmacology, Immunology, Pathology, Internal medicine, Central nervous system, PsychiatryTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
3Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 3Per-year citation counts (last 5 years)
- References (count)
-
79Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.Alzheimer’s | 0 |
| abstract_inverted_index.Pharmacologic | 140 |
| abstract_inverted_index.blood–brain | 35 |
| abstract_inverted_index.characterized | 132 |
| abstract_inverted_index.dehydrogenase | 63 |
| abstract_inverted_index.BBB-associated | 89 |
| abstract_inverted_index.broad-spectrum | 230 |
| abstract_inverted_index.pathologically | 21 |
| abstract_inverted_index.neuroprotective | 183 |
| abstract_inverted_index.anti-inflammatory | 72, 217 |
| abstract_inverted_index.indistinguishable | 177 |
| abstract_inverted_index.neurodegeneration | 169 |
| abstract_inverted_index.neurodegenerative | 11 |
| abstract_inverted_index.neurodegeneration, | 126 |
| abstract_inverted_index.neuroinflammation, | 124, 157 |
| abstract_inverted_index.15-hydroxyprostaglandin | 62 |
| cited_by_percentile_year.max | 97 |
| cited_by_percentile_year.min | 96 |
| countries_distinct_count | 3 |
| institutions_distinct_count | 49 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
| sustainable_development_goals[0].score | 0.8399999737739563 |
| sustainable_development_goals[0].display_name | Good health and well-being |
| citation_normalized_percentile.value | 0.94421561 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | True |