Exploring the role of the oncogene Dek as a novel player in Alzheimer’s disease.
Neurocognitive disorders (including Alzheimer’s disease) currently affect 35 million people in the United States. These disorders exact a significant emotional, physiological, and financial toll on the individual and the individual’s social network. As such, understanding the precipitating and exacerbating factors of cognitive impairment is a pressing medical health issue. An important step towards understanding factors that contribute to cognitive dysfunction is identifying mechanisms that can prevent or delay the progression of cellular and molecular pathologies in the brain that lead to cognitive dysfunction. This LIFE Foundation application proposes that the chromatin remodeling Dek oncogene serves as an important cognitive protective factor in the brain. This postulate is based on published and preliminary data from the Principal Investigators (Dr. Solomon and Dr. Privette-Vinnedge). Dr. Privette-Vinnedge (cancer biologist) has determined that Dek is expressed in proliferating cells. She has also determined that Dek loss in the periphery (breast cancer cells) is associated with DNA damage, cellular senescence, apoptosis, and down-regulation of WnVj3-catenin signaling, a critical molecular pathway for learning and memory. Notably, these cellular and molecular anomalies following Dek depletion occur in neurodegenerative diseases like Alzheimer’s. Currently, our knowledge regarding Dek signaling is limited to the periphery. Dr. Solomon’s (behavioral neuroscience) laboratory is the first to describe the distribution of Dek in the adult rodent brain specifically in cortico-limbic regions associated with learning and memory. Dek is heavily expressed in the dorsal and ventral hippocampus and is co-expressed with all major cell types in the hippocampus including neurons, astroglia, and microglia. Dek is also expressed in the amygdala, entorhinal, and medial prefrontal cortices. Preliminary data from our group indicate that Dek deficient mice have impaired attention and object recognition, suggesting a functional role for Dek in learning and memory. Gene ontology analysis of human cells using ToppGene identified Alzheimer’s disease as a candidate Dek loss-associated disease, further suggesting that Dek is critical for learning and memory.
Exciting and newly generated data from our laboratory indicates that similar to rodents, Dek is expressed in the dorsolateral prefrontal cortex in human brain. On the bases of these findings, the current proposal tests the overarching hypothesis that Dek signaling in critical cortico-limbic brain regions is necessary for learning and memory. We will test this hypothesis in three aims. Aim 1 delineates the role of Dek signaling on cellular and molecular pathologies associated with Alzheimer’s disease using human and murine hippocampal and cortical cell lines. Aim 2 delineates the role of Dek signaling in rodent medial prefrontal cortex on cellular and behavioral hallmarks of learning and memory in vivo. Aim 3 further characterizes Dek expression in the human dorsolateral prefrontal cortex. Results from these studies are poised to advance our understanding of neural mechanisms associated with cognitive impairment. In addition, the findings may identify Dek as an important protective factor for brain health and as a novel target for the treatment of neurocognitive disorders.
Matia B. Solomon, PhD
Matia Solomon received her PhD in Behavioral Neuroscience from Georgia State University in Atlanta GA in 2006. She later began her post doctoral fellowship at the University of Cincinnati in the Department of Psychiatry and Behavioral Neuroscience where she studied the impact of chronic stress on brain function and depression in males and females. She is currently the Principal Investigator of the Social and Affective Neuroscience Laboratory at the University of Cincinnati where her research team investigates how stress and gonadal hormones influence depression and cognitive function in males and females. She relies on nonsocial and social based assays to gauge emotionality and cognitive function. She has published over 35 scientific research papers, 2 book chapters and over 100 scientific research abstracts mainly focusing on sex differences in stress related conditions including depression-like behavior and obesity. She has won several awards including the Elizabeth Young Outstanding New Investigator Award for her research on sex differences in depression-like behavior using brain specific genetic mouse models from the Organization for the Study of Sex Differences. In 2013, Dr. Solomon was also selected to represent the University of Cincinnati as an Emerging Minority Faculty Scholar.
Lisa Privette Vinnedge, PhD
Lisa Privette Vinnedge completed her B.A. degree at Miami University (OH), majoring in Microbiology and Classical Humanities with a minor in Molecular Biology. She then earned her M.S. and Ph.D. degrees in Human Genetics from the University of Michigan, with a focus on cancer biology and genetics. Since this time, she has studied the molecular drivers of breast cancer progression and metastasis while collaborating with several investigators to also identify blood biomarkers of cancer and perform preclinical testing of novel cancer therapeutics. Her cancer biology research has been supported by numerous agencies, including the NIH, Department of Defense, and the Marlene Harris Ride Cincinnati Foundation. This unique collaboration between a molecular cancer biologist and a behavioral neuroscientist stemmed from a common interest in the influence of hormones on human biology and the understanding that the proteins and cellular processes that are “turned on” to drive cancer are often “turned off” in Alzheimer’s disease and other neurocognitive disorders.