Inhibition of 15-PGDH Preserves Blood–Brain Barrier Integrity in Alzheimer’s Disease and Traumatic Brain Injury

UH Research & Education Institute

An innovative collaboration between colon cancer and neurodegeneration researchers has led to a groundbreaking discovery that could transform how Alzheimer’s disease (AD) and traumatic brain injury (TBI) are treated.

Sanford Markowitz, MD, PhD

Andrew A. Pieper, MD, PhD

Sanford Markowitz, MD, PhD, an internationally recognized cancer geneticist, and Andrew A. Pieper, MD, PhD, an internationally recognized psychiatrist and neuroscientist, have discovered that inhibiting the enzyme 15-PGDH can preserve brain health and slow neurodegeneration in these two conditions. The researchers co-lead a multi-institutional collaboration and have been working together for six years to identify novel drug targets to effectively prevent or slow neurodegeneration by targeting the blood–brain barrier (BBB). They have identified 15-prostaglandin dehydrogenase, or 15-PGDH, an enzyme that controls inflammatory signaling, as a potential drug target for protecting the brain and fighting neurodegenerative disease.

“We have two physician-scientists, a colon cancer doctor and a psychiatrist, here at University Hospitals collaborating on ways to protect the brain from Alzheimer's disease and traumatic brain injury by targeting a very interesting enzyme,15-PGDH,” says Daniel I. Simon, MD, President, Academic & External Affairs and Chief Scientific Officer, and Ernie and Patti Novak Distinguished Chair in Healthcare Leadership at University Hospitals. “This breakthrough comes from their combined expertise in two very different specialties.”

Significantly, Markowitz and Pieper were recently honored with the prestigious Proceedings of the National Academy of Sciences (PNAS) Cozzarelli Prize, for PNAS “Paper of Year” in biomedical sciences. This recognition from the Editorial Board of the Proceedings of the National Academy of Sciences USA highlights their outstanding scientific contribution and the impact of their research on protecting the blood–brain barrier and advancing understanding of the pathophysiology of neurodegeneration in AD and TBI. This groundbreaking research has demonstrated that inhibiting 15-PGDH blocks blood–brain barrier deterioration and protects mice from a wide array of pathological events normally seen in AD and TBI, including cognitive impairment.

Scientific Collaboration Amplifies Potential Broad-Reaching Impact of Novel Research

To break new ground in the treatment of cancer and neurodegenerative disease, Drs. Markowitz and Pieper are innovatively combining their expertise in genetics and psychiatry to reshape how we think about inflammation and neuroprotection in fighting conditions like colon cancer and Alzheimer’s disease.

Dr. Markowitz holds the Markowitz Ingalls Professorship of Cancer Genetics and is a Distinguished University Professor at Case Western Reserve University (CWRU) School of Medicine, with appointments in the Department of Medicine and in the Case Comprehensive Cancer Center. He is internationally recognized for his work identifying key genetic causes of colon cancer and developing molecular tests for early cancer detection. In clinical practice, he is an attending physician at the University Hospitals Seidman Cancer Center.

Dr. Pieper is a board-certified psychiatrist and neuroscientist in the Department of Psychiatry at CWRU and University Hospitals Cleveland Medical Center, where he holds the Rebecca E. Barchas MD DLFAPA CWRU Professorship in Translational Psychiatry and the UH Morley-Mather Chair in Neuropsychiatry. He also serves as a geriatric psychiatrist at the Louis Stokes Cleveland VA Medical Center and is an investigator at UH’s Harrington Discovery Institute, where he is the Director of the Center for Brain Health Medicines. He is internationally recognized for his pioneering work in understanding and developing new treatments for neuroprotection in brain injury and disease.

Prior to this collaborative research with Dr. Pieper, Dr. Markowitz and his team had previously determined that 15-PGDH promoted inflammation in the colon. With support from the Harrington Discovery Institute, they had developed a small molecule drug that could block 15-PGDH enzyme activity and showed that this molecule could activate stem cells to protect the colon from ulcerative colitis and to accelerate tissue healing in diseases of multiple other peripheral organs. As the research progressed, Dr. Markowitz and Dr. Pieper connected via a mutual colleague and gave thought to the possibility of treating or preventing brain inflammation in neurodegenerative disease by targeting 15-PGDH in the BBB.

Fighting Inflammation by Targeting 15-PGDH Becomes Common Research Thread

“We found that 15-PGDH activity was especially enriched in a population of cells within the blood-brain barrier, and that this caused inflammation that damages this structure that normally serves to protect brain health,” says Dr. Pieper. “Our results showed that pharmacologic or genetic inhibition 15-PGDH protected the blood-brain barrier from this damage, which in turn enabled the brain to remain health and withstand the stress of injury or genetic disease. Strikingly, this new approach achieved complete protection in animal models of Alzheimer’s disease without affecting the classical amyloid plaque pathology that is currently targeted by therapeutics in the field. This demonstrates proof pf principle that reducing amyloid plaque may not be necessary for effective treatment of Alzheimer’s patients and is also compatible with the observation that many people accumulate Alzheimer’s-like levels of amyloid plaque in their brain without ever developing any symptoms of dementia.”

The researchers have likewise determined that inhibiting 15-PGDH can also protect the brain from neurodegeneration following a traumatic brain injury. “We have developed a rigorous and highly clinically relevant mouse model of traumatic brain injury that faithfully recapitulates the injury complexity and a lot of the acute and chronic effects of traumatic brain injuries in patients,” says Dr. Pieper. “We found that if we start inhibiting 15-PGDH within 24 hours of a traumatic injury on a mouse, we can preserve the blood-brain barrier and prevent many of the problems that would otherwise arise after TBI, including complete protection from cognitive impairment.”

The most recent findings on this research appear in the May 21, 2025, issue of PNAS in an article titled, “Inhibiting 15-PGDH blocks blood-brain deterioration and protects mice from Alzheimer’s disease and traumatic brain injury.” In the publication, the researchers explain how 15-PGDH levels are elevated in human and mouse Alzheimer’s disease, traumatic brain injury (TBI), and aging, with 15-PDGH located in the myeloid cells of the BBB. According to the research, pharmacologic and genetic inhibition of 15-PGDH protects the BBB. It does this by blocking production of reactive oxygen species by brain myeloid cells, that prevents brain damage and neurodegeneration, thereby preserving cognition in mouse models of AD and TBI. The findings provide a basis for an innovative therapeutic approach for AD and TBI by administering drugs that inhibit 15-PGDH to protect the BBB.

15-PGDH inhibitors are now being targeted by several pharmaceutical and biotech companies. Drs. Markowitz and Pieper hope that their new studies will translate to clinical trials of this emerging class of new drugs for treating patients with Alzheimer’s or TBI.

Learn more about this research and watch The Cozarelli Prize video >