Research
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 clinical 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.
Epigenetic Regulation in Aging and Alzheimer’s Disease
(1R01AG079989-01, PI: Dong, 12/15/2022 – 11/30/2027)
Aging is a major factor in the development of sporadic Alzheimer’s disease (AD) but the mechanisms underlying this risk are not well understood. Epigenetics has been involved in both aging and AD processes. Promising results from our group and others have shown that epigenetic alteration occurs during aging and affects neuronal function. Dysregulation of epigenetics contributes to memory deficits and AD-related pathogenesis. However, whether epigenetic dysregulation in the brain can drive normal aging toward AD has not been investigated. In this proposed project, we will use animal models of aging and AD, as well as human postmortem tissues and existing datasets to determine the dynamic changes of the histone modification in epigenome during aging and whether these changes can endorse AD development and/or progression. Our overall hypothesis is that dysregulations of histone modification in memory and AD-related pathways during aging can promote AD by initiating and/or furthering AD pathogenesis and memory impairment; thus, histone deacetylase (HDAC) inhibitors could prevent and/or alleviate such changes and prevent AD development and progression. Our goal is to reveal the epigenetic mechanisms that bridge aging and AD and identify the druggable targets that will help to develop novel therapeutic strategies for the prevention and treatment of AD.
Estrogen signaling linked to stress and Alzheimer’s Disease
(1 R01 AG078386-01, Resubmitted)
Women are more vulnerable to Alzheimer’s disease (AD) and stress-related psychiatric disorders such as anxiety and depression. Both stress and depression increase the risk of developing AD. However, the biological mechanisms underlying the sex-specific vulnerability of neuropsychiatric disorders remain unknown. Our previous publications and preliminary data strongly suggest that sex differences in the response to chronic stress is one of the factors that could cause women to develop AD, and estrogen-driven mechanisms underlie this vulnerability. We will continue to advance this line of important work in the proposed project. We hypothesize that reduction of estradiol levels and selective alteration of estrogen signaling during menopause markedly enhance the vulnerability of women to AD, particularly under stress conditions. The goal of our proposed project is to reveal the mechanistic link of the changes of estrogen signaling pre-, peri- and post-menopause to brain function, stress, and AD, and whether selective estrogen receptor agonists could mitigate any negative effects. Hopefully, through this work, we can find novel therapeutic targets that could potentially reduce the vulnerability of women to AD, as well as stress-related psychiatric disorders.
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 remain 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 show 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 the 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.