Research in the Laboratory of Translational Neurobiology started in 2000 and led by Principal Investigator Dr. Hongxin Dong MD PhD, focuses on the interaction of genetic and environmental influences on neurodevelopment and aging and their relevance to the pathogenesis of neuropsychiatric disorders, particularly Alzheimer’s Disease (AD). The goal of our research program is to use both clinic data (premortem clinical assessments and postmortem tissues analyses) and animal models (established and new animal models) to discover novel molecular, genetic, and epigenetic mechanisms and their interactions underlying neuropsychological symptoms in AD. Our research aligns with the development of therapeutic strategies to delay disease onset and/or slow disease progression. Importantly, the laboratory is also an education center in which many undergraduate students, graduate students, and postdoctoral fellows train to become successful, independent research faculty, highly-skilled clinicians, and leaders in industry, both nationally and internationally. Our commitment to scientific discovery and education will further our understanding of neurobiology during aging and impact the treatment of neuropsychiatric disorders in the future.
Currently the major ongoing projects in the laboratory are:
Molecular Mechanisms Underlying Behavioral and Psychological Symptoms in Alzheimer’s Disease
(1R01AG062249-01, PI: Dong, 09/15/2017 – 06/30/2023)
AD is characterized by memory loss and other cognitive deficits, but up to 90% of AD patients develop behavioral and psychological symptoms of dementia (BPSD) during the course of the disease, and the mechanism(s) underlying this etiology is unknown. In this project, by collaborating with Drs. Robert S. Wilson and David A. Bennett at Rush University Alzheimer’s Disease Center, we started investigating whether BPSD domains are being regulated by specific genes and their related signaling pathways. This translational project will be performed with a data-driven approach (RNA-seq and bioinformatics analyses) to characterize the signaling pathways that regulate the specific domains at both the clinical (behavioral assessments and postmortem tissues) and preclinical (animal models of AD with BPSD-like behavior) levels. We aim to establish a translational pipeline by associating BPSD domains with molecular alterations in human patients with AD and test the causal relationship of these elements in mouse models. Achieving these goals will lead to a better understanding of BPSD in AD and, hopefully, identify novel targets for future therapeutics.
Sex Differences in Central Stress Response and Alzheimer’s Disease Neuropathology
(1RF1AG057884-01, PI: Dong, 09/15/2017 – 06/30/2022)
The total Alzheimer’s patient population is now estimated to be over 45 million worldwide, and two thirds of those afflicted are women. Yet, very little is known about why more women are affected by the disease than men. Though it was once thought that longer lifespan led to a greater proportion of AD patients being women, newer research suggests women may also be at higher risk of the disease. This project will examine how the unique female response to stress, specifically through the corticotrophin releasing factor (CRF) signaling pathway, contributes to the increased risk for AD. The information derived from this project will help to develop new treatment and prevention strategies that benefit both sexes.
Our previous work has demonstrated a strong relationship between stress and cognitive decline in AD patients, as well as providing some insight into the complex interactions between behavioral stressors, stress mediators, and Aβ metabolism in AD animal models. We have identified CRF and CRF receptor 1 (CRF1) as central mechanisms mediating the impact of stress on AD pathology. Using a phosphoproteomic approach, we recently determined that there are sex-specific biochemical differences in downstream CRF1 signaling that can lead to increased AD pathology in females compared to males. With NIH R56 bridge funding (1R56AG053491-01), we were able to pursue this idea further and have begun to determine the mechanisms underlying the interaction between sex-specific CRF1-PKA activation and the pathogenesis of AD.
Age-Related Histone Modification Effect on Antipsychotic Action
(1R01MH109466-02, PI: Dong, 05/26/2016 – 02/28/2021)
Aging induces remarkable changes in the CNS of humans and other mammals, from neural circuits all the way down to the genomic level, and it is possible that these changes undermine the capacity of older individuals to respond to psychotropic drugs. For antipsychotics, the increase in side effects and decreased efficacy in elderly patients is especially troubling, and a FDA-administered black box warning exists for these drugs due to the increased risk of mortality in this population. The pharmacokinetic and pharmacodynamic alterations in aged population have been profoundly investigate, but the ability of epigenetic mechanisms to influence the efficacy of drug treatments in the aged brain is unknown. In this project, we seek to confirm the novel epigenetic mechanisms underlying the regulation of antipsychotic action during aging and determine whether histone deacetylase inhibitors (HDACis) could be used to improve antipsychotic treatment in the elderly.
Our central hypothesis is that age-related increases in motor side effects of antipsychotics are due to histone hypoacetylation on their targeted receptor genes and that these epigenetic alterations and their functional consequences can be reversed by co-treatment with HDACis. The proposed studies will greatly advance our understanding of a novel mechanism by which age-related histone modification alters antipsychotic action. This paradigm will have implications not only for antipsychotic medication but also for other pharmacological approaches in geriatrics. For example, we extended this project to examine the epigenetic mechanisms underlying delayed recovery after general anesthesia in aged animal models.
Multifaceted Role of PAI-1 in Neurocognitive Aging and Alzheimer’s Disease
(PPG project – the proposal is prepared for submission)
Age is a major risk factor for neurodegenerative diseases, particularly Alzheimer’s disease (AD). However, the molecular triggers that inform the transition from normative aging to AD pathology remains uncertain. Several groups have demonstrated that plasmin, a serine protease whose activation is inhibited by plasminogen activator inhibitor-1 (PAI-1), is involved in the degradation of Aβ, and that chronically elevated Aβ peptides in the brain correlate with the upregulation of PAI-1 and functional inhibition of the tPA-plasmin system. Conversely, genetic deletion of the PAI-1 gene or pharmacological inhibition of PAI-1 leads to increased tPA-plasmin activity and reduces the amount Aβ plaques in the brain of APP/PS1 mice. In collaboration with Dr. Vaughan in the Department of Internal Medicine, we will explore how PAI-1 may affect AD pathogenesis and if PAI-1 inhibition is a viable treatment strategy.
Through a long-term investigative program investigating the molecular regulation of plasminogen activator inhibitor-1 (PAI-1) and its role in vascular biology and aging, Dr. Vaughn has demonstrated that PAI-1 is not only a marker of aging but also an important mediator of aging-related morbidity, including neurodegenerative diseases. Dr. Vaughan’s group has completed a phenotypic characterization of approximately 2% of a unique kindred of Old Order Amish individuals harboring a loss of function mutation in the gene encoding PAI-1 (SERPINE1). They found that carriers of the mutant allele have a longer median lifespan, in addition to improved metabolism, protection from diabetes, and preserved vascular flexibility, supporting the relevance of PAI-1 in the biology of aging in humans. Importantly, our recent preliminary data shows that treatment of APP/PS1 mice with an orally-active small molecule PAI-1 inhibitor (TM5A15) leads to decreased amyloid plaque deposition, increased active BDNF in cortical tissue, and improved memory. We hypothesize that PAI-1 plays a multifaceted role in AD through promotion of senescence and Aβ accumulation. We will further investigate: 1) the effects of the “Amish -PAI-1” mutation itself on memory and cortical pathology in APP/PS1 mice; 2) the effects of partial or complete PAI-1 deficiency on neuronal biology and senescence using iPSCs from defined humans donors (SERPINE1+/+ , SERPINE1+/- , or SERPINE1-/-); 3) the impact of cell-specific PAI-1 knockouts (endothelial vs astrocyte) in APP/PS1 mice; 4) the ability of small molecule PAI-1 inhibitors to reverse AD-like pathology and rescue cognitive function in APP/PS1 mice.