Investigation of the Novel Role of 15-Hydroxyprostaglandin Dehydrogenase in Neurodegeneration in a Mouse Model of Alzheimer's Disease
Alzheimer’s disease (AD) is one of the most highly prevalent and devastating conditions in society, and there are currently no treatments that prevent or slow disease progression. We have discovered a new biological system governing neurodegeneration in traumatic brain injury: enzymatic activity of 15-prostaglandin dehydrogenase in the brain that controls levels of prostaglandin E2, an endogenous agent that protects neurons. We also have preliminary evidence that levels of 15-PGDH are pathologically increased in animal models of AD, as well as human AD brain. This project will rigorously determine whether this aberrant increase in 15-PGDH plays a causative role in nerve cell death and behavioral learning problems in a mouse model of AD and could thus identify a new therapeutic target for patients.
Alzheimer’s disease (AD) is one of the most highly prevalent and devastating conditions in society, and there are currently no treatments that prevent or slow disease progression. Traumatic brain injury (TBI) is one of the strongest non-genetic risk factors for AD, and I have discovered a new biological system in the brain governing neurodegeneration in TBI: enzymatic activity of 15-prostaglandin dehydrogenase (15-PGDH). 15-PGDH activity degrades prostaglandin E2, an endogenous agent that is normally present to protect neurons. I have also discovered that levels of 15-PGDH are pathologically increased in animal models of AD, as well as in human AD brain. This project will rigorously determine whether the aberrant increase in 15-PGDH plays a causative role in nerve cell death and cognitive deficits in a mouse model of AD. If so, then inhibition of 15-PGDH with drugs related to the 15-PGDH inhibitor I am testing here could provide a new therapeutic agent to treat patients with AD, or to protect patients from developing AD after TBI.
About the Researcher
Min-Kyoo Shin, PhD, is a postdoctoral research associate at Case Western Reserve University in the Department of Psychiatry, working in the laboratory of Dr. Andrew A Pieper, who also serves as Director of Neurotherapeutic Discovery in the Harrington Discovery Institute of the University Hospitals of Cleveland Medical Center. Min-Kyoo earned his bachelors, masters and philosophy degrees from Sungkyunkwan University in South Korea, where he studied biology and neuroscience. There, Dr. Shin’s research focused on discovery of novel peptides that regulate brain-derived neurotrophic factor (BDNF) expression. BDNF plays an important role in neuronal cell survival, neurogenesis and cognition, and its expression is down-regulated in neurodegenerative diseases such as AD. Several novel peptides were identified through a positional scanning-synthetic peptide combinatorial library technique, and exposure of cellular and animal models of AD to these peptides was shown to have neuroprotective effect. Dr. Shin also investigated the neuronal function of gangliosides in AD, finding that GQ1b, a low abundant ganglioside, regulates N-methyl-D-aspartate (NMDA) receptor signaling to control synaptic plasticity and memory. In addition, GQ1b, but not GT1b or GD1b derived from GQ1b by membrane sialidase, regulated BDNF expression via the NMDA receptor signaling pathway. As a postdoctoral fellow at Sungkyunkwan University, Dr. Shin demonstrated that intrahippocampal GQ1b infusion ameliorates cognitive impairments in an AD mouse model. Dr. Shin has devoted his career in medical research to the discovery of novel neuropathological mechanisms of AD that will expand our understanding of the disease process and also identify new therapeutic opportunities for patients. In the Pieper lab, Dr. Shin is continuing to develop this focus by investigating the novel role of 15-prostagrandin dehydrogenase in neurodegeneration in a mouse model of AD.
As a child, my dream was to become a doctor to supply medical aid to those lacking access to medical treatment. With this goal, I chose biology as my undergraduate major. However, in the summer of my sophomore year, I started a research internship in a basic science laboratory, and became passionately interested in medical research. The topic of how the human brain functions to create or erase memories captivated me, which evolved into a growing interest to the Alzheimer’s disease. This was a fork in the road for me, and I continued working in this laboratory until graduation. At that time, I had to decide whether to pursue medical school or graduate school, and I sought advice from a senior researcher who told me, “You can become a doctor and treat those in need. However, you could become a researcher and if your research could unveil a new method of treatment then you could treat millions of those who are in need.” His inspirational advice gave me a new sense of commitment, and to this day I am currently working to advance our understanding in Alzheimer’s disease with the ultimate goal of developing new treatments for patients. I am most grateful for the financial support provided by the BrightFocus donors, who have given me the opportunity to investigate the role of 15-PGDH in AD, which I believe has great potential for advancing the treatment of patients with AD.
First published on: November 12, 2019
Last modified on: November 12, 2019