Functional Significance of DEK in Alzheimer’s Disease and Age-Related Dementias
This LIFE proposal tests the overarching hypothesis that the chromatin-remodeling nuclear phosphoprotein, DEK, is an important cognitive protective factor in the brain and that its deficiency in the central nervous system (CNS) induces cognitive impairment. We have gathered compelling in vitro and in vivo data linking DEK expression with learning and memory in rodents and humans that warrant further investigation into the role of this transcription co-factor in cognitive function. Gene ontology analyses (ToppGene) identified Alzheimer’s disease (AD) and other cognitive diseases (e.g., age-related cognitive decline, presenile dementia) as candidate diseases associated with loss of DEK expression. Consistent with this, in human postmortem brain tissue, relative to age-matched controls, we found lower cortical DEK protein expression in elderly, post-menopausal women with severe dementia, but not in elderly men with dementia, suggesting a sex-specific link with DEK and dementia. Our preliminary data in rodents indicate that ovariectomy (surgical menopause) or the presence of ApoE4 allele (greatest genetic risk factor for AD), are associated with decreased cortical and hippocampal DEK expression in female rodents. These findings are the first to link DEK Joss with biological and genetic risk factors for dementia and AD. Further, female whole body DEK knockout mice have deficits in object recognition memory, suggesting a functional role for DEK in learning and memory. We recently published the first study characterizing the neuroanatomical distribution of DEK in the adult murine central nervous system (CNS). DEK is prominently co-expressed with neurons in the murine hippocampus, a critical region for learning and memory. We have also determined that DEK deficiency in neuronal cell lines induces cellular and molecular anomalies linked to AD. Collectively, our findings indicate a neurocognitive protective effect of DEK in the brain, and thus the hypothesis is that DEK deficiency in the CNS induces cellular, molecular, and behavioral anomalies associated with cognitive dysfunction. In Aim 1, we will use cell culture models to identify the molecular mechanism by which DEK loss of function in neurons gives rise to cellular and molecular anomalies associated with AD neuropathology or other dementias. We will also use these models to begin to understand how DEK expression is neuroprotective. In Aim 2, we will test the hypothesis that DEK is necessary for learning and memory in the adult brain with the creation of a newly developed DEK conditional knockout mice, wherein we will spatially and temporally control DEK expression in distinct forebrain neurons in male and female mice. We will assess the functional consequences of DEK in learning and memory using a battery of cognitive based behavioral tests. Finally, in Aim 3 we will further query the association of DEK with dementia severity and AD neuropathology in men and women by using existing data in clinically relevant populations. The inclusion of males and females in each aim (i.e., cells, rodents, and humans) of this proposal allows us to gather data to confirm that sex differences with regards to the impact of DEK on cognitive function exist. This research strategy sets the stage for future studies to examine the mechanisms for these potential sex differences. Collectively, these findings may pinpoint DEK as an important neuroprotective factor for brain health and as a novel target for the treatment of AD and/or other dementias.
Matia B. Solomon, Ph.D
Matia Solomon received her PhD in Behavioral Neuroscience from Georgia State University in Atlanta GA in 2006. She later began her postdoctoral 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.