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Current Trainees

Photo Name Project Mentor Email
Aponte Confesi, Luis Alberto Alzheimer's disease (AD) is characterized by progressive memory loss and cognition. The process of adult hippocampal neurogenesis is integral for the process of memory formation in the hippocampus and has been shown to be impaired in patients with AD. Our research focuses on elucidating the role of PICALM, one of the top three risk factor genes for the development of late onset Alzheimer's Disease (LOAD), in regulating the process of adult hippocampal neurogenesis in LOAD. In order to study this, we will use vascular permeability assays alongside magnetic resonance imaging, and cranial window imaging in AD animal models to better understand how PICALM affects adult hippocampal neurogenesis. This project will help elucidate novel information of how PICALM regulates development of LOAD. Orly Lazarov, Ph.D. and Ciro Ramos-Eztebanez. M.D., Ph.D. lapont5@uic.edu
Maldonado Weng, Juan Enrique The gut microbiome (GM) is a modifiable metabolic organ, composed of gastrointestinal bacteria, emerging as an important component in Alzheimer’s disease (AD) pathology. AD patients exhibit dysbiosis, a decrease in beneficial bacteria with an increase in toxic species. However, it remains unclear how the universal biological variables (UBVs) of AD risk (age, APOE genotype, and sex) affect the GM metabolic function. Our hypothesis is that a dysbiotic GM disrupts metabolic processes exacerbating UBV-driven AD pathology. Therefore, we will evaluate the interactive effects of age with APOE and sex on the GM of 4-month (M) and 8M EFAD transgenic mice by 16s rRNA gene amplicon sequencing. We will then examine the effects of APOE and sex on the metabolic functions of 8M EFAD GM by shotgun metagenomics. Ultimately, my project is designed to identify compositional profiles and metabolic phenotypes of the EFAD GM induced by AD-like pathology and modified by UBVs. Mary Jo LaDu, Ph.D. and Jie Lang, Ph.D. jmaldo27@uic.edu
Nowar, Raghd Mohamed Therapeutic targeting of tau, in contrast to Aβ, has not been widely explored in clinical trials. Recent findings provide new insight into tau pathology: Exposure of a 17 amino acid N-terminal sequence of tau that is sequestered in normal brain appears to be necessary that comprises a Phosphatase Activation Domain (PAD). PAD acts as biologically active motif that is sufficient to activate a signaling pathway that is associated with the inhibition of fast axonal transport and toxicity in neurons. The monoclonal antibody (TNT1), specific for the PAD-tau epitope, blocks toxic effects of pathogenic tau. Therefore, PAD provides a molecular basis for altered kinase activities in AD and tauopathies and represents a novel therapeutic target. We are developing cell-based analytic assays for validation of target engagement of identified PAD small molecule ligands in neurons and phenotypic assays for establishing therapeutic efficacy in primary cultured neurons that are important for optimization and in vivo dose response of candidate compounds in neurons. Scott Brady, Ph.D. and Terry Moore, Ph.D. rnowar2@uic.edu
Snead, Amanda Mary Our research investigates whether dysfunction in the autophagic lysosomal pathway contributes to AD pathogenesis and if increasing autophagic flux in AD neurons will alleviate AD-like pathology and reduce neuronal loss. We will test this by first determining the nature of alteration to autophagic lysosomal pathways in human AD neurons derived from induced pluripotent stem cells (iPSCs) carrying the amyloid precursor protein Swedish and Presenilin 1 M146V Familial AD mutations. We will then test modulation of autophagy in this model. This project will help to determine the efficacy of autophagy modulation in relieving pathologies observed in AD and shed light into the therapeutic potential of autophagy in AD. Swetha Gowrishankar, Ph.D. asnead2@uic.edu

Previous Trainees

Photo Name Project Mentor Email
Gordon-Blake, Jesse We are developing small molecule nicotinamide phosphoribosyltransferase (NAMPT) positive allosteric modulators (N-PAMs) for the treatment of Alzheimer's Disease (AD). Neuronal dysfunction in AD and aging is closely tied to mitochondrial function and physiological deficits caused by dysfunctional mitochondria have been shown to play a major role in Aβ-induced toxicity. Aging is the single greatest risk factor for the development of AD and age-dependent nicotinamide adenine dinucleotide (NAD) depletion is observed in the human brain. Restoration of depleted NAD improves multiple cellular systems perturbed in AD models, including mitochondrial function, thereby representing a therapeutic strategy capable of addressing the Aβ burden and neuronal dysfunction. NAMPT catalyzes the rate-limiting step in NAD biosynthesis and so presents a viable target for NAD enhancement. N-PAMs were identified by high throughput screen (HTS) and optimization in ongoing. HTS hits and analogs show neuroprotection and prevent NAD depletion in vitro. Optimized compounds will be assessed for their effect on mitochondrial function and protection from Aβ. We expect to develop potent and efficacious N-PAMs that boost NAD and improve Aβ-induced mitochondrial dysfunction. Tom Driver, Ph.D. jgordo27@uic.edu
Sotelo, Daniel There is a growing general consensus that the autophagy-lysosome pathway is disrupted in AD and other forms of neurodegeneration. Induction of autophagy with small-molecule activators can increase the rate of protein aggregate clearance, such as those generated from APP and MAPT. Through a GFP-LC3 HCS, we discovered and developed two novel autophagy activators that modulate autophagy in an mTOR-independent manner. These activators are undergoing target validation studies and will also be optimized to improve ADME-Tox properties. The activators will then be tested for their efficacy in alleviating Aβ-induced autophagic disruption in an in vitro model. Neurotoxic and neuroinflammatory aspects of AD will be modeled in a co-culture system containing i3 neurons exposed to oligomeric Aβ for different time periods. It is expected that oligomeric Aβ will induce accumulation of autophagic vacuoles (AVs), ineffective retrograde axonal transport, and neuronal loss, which may be relieved by our autophagy activators. Leslie Aldrich, Ph.D. dsotel2@uic.edu
Knopp, Rachel Dysfunction of calcium homeostasis is widely reported to contribute to synaptic degeneration in AD. This imbalance leads to the hyper-activation of two cysteine proteases: calpain-1 and cathepsin B. The over-activation of these proteases have been proposed as underlying contributors not only to AD, but also to traumatic brain injury (TBI) and ischemic stroke (IS). The goal of this research is to determine an optimal strategy for targeting these proteases in treatment of neurodegenerative disorders, while also further elucidating the mechanisms by which they contribute to AD. Greg Thatcher, Ph.D. rknopp3@uic.edu
Le, David Hemodynamic changes in response to neural activity, termed as neurovascular coupling, is essential for cerebral blood flow (CBF) regulation in normal brains. Recent studies have associated Alzheimer’s disease (AD) with early neurovascular dysfunction. However, direct access to the brain for monitoring neurovascular coupling defects is difficult. The retina, a complex structure within the eye is composed of an intricate network of neurons and blood vessels, is part of the central nervous system (CNS) and is also affected by AD neurovascular dysfunction. Recent studies have revealed the presence of β-amyloid plaques and tau proteins, key biomarkers of AD, in the retina as well. The retina, coined as the “window into the brain”, can be monitored noninvasively using optical coherence tomography (OCT) and OCT angiography (OCTA). Our research aims to use OCT and OCTA for high-resolution non-invasive monitoring of AD neurovascular dysfunction within the retina. Xincheng Yao, Ph.D. and Orly Lazarov, Ph.D. dle45@uic.edu
Rakowiecki, Karen Fifty percent of patients with Down Syndrome (DS) will develop Alzheimer’s Disease (AD) by the time they reach the age of sixty. It is theorized that the additional gene copy of APP as a result of trisomy of chromosome 21 contributes to this early onset, aggressive form of AD. To investigate whether APP gene copy number contributes to altered gene expression and AD pathology in DS, we will apply CRISPR-Cas9 technology to eliminate one copy of APP from DS patient-derived induced pluripotent stem cells (iPSCs). Utilizing this cell line, I will look at changes in APP processing, neuronal maturation, and neurogenesis and investigate phenotypic alterations as potential small molecule drug targets. These experiments will further elucidate the role of APP and contribute to the development of potential therapeutics for AD in DS. Orly Lazarov, Ph.D. and Greg Thatcher, Ph.D. krakow2@uic.edu
Stephen, Terilyn Recent studies have established that several of the late-onset Alzheimer’s Disease (LOAD) risk factor genes identified by genomic wide association studies contribute to neurovascular regulation. The goal of this research is to understand the contribution of PICALM, one of the top three LOAD risk factor genes, in endothelial cell dynamics and dysfunction at the blood brain barrier. I will use multi-photon analysis, vascular permeability assays, and proteomic approaches to determine the effect of endothelial PICALM loss on vascular function and structure in AD animal models and human iPSCs derived brain microvascular ECs. These experiments will be instrumental in providing novel insight into the role of PICALM in AD development and help establish therapeutic interventions for LOAD. Orly Lazarov, Ph.D. and Stephanie Cologna, Ph.D. tsteph2@uic.edu
Karstens, Aimee We are quantifying plasma lipoprotein profiles using size exclusion chromatography in the context of a Mediterranean Diet intervention to improve cognition in female obese older adults, and additionally examining the effect of APOE4, the greatest genetic risk for Alzheimer’s Disease, on the efficacy of the the intervention (i.e., improving cognition and plasma lipoprotein profiles). The plasma lipoprotein profile is established by the elution of the lipoproteins from a size exclusion column, with the larger, lipid-laden chylomicrons and very low density lipoproteins eluting first, followed by low density lipoproteins, high density lipoprotein (HDL)-2, HDL-3, and then free protein. Using the fractions fast protein liquid chromatography, we can further quantify lipids (e.g., cholesterol) and other particles (e.g., oligomeric amyloid beta). Mary Jo LaDu, Ph.D. and Scott Langenecker Ph.D. karsten2@uic.edu
Lewandowski, Cutler We aim to identify and develop tissue-selective ABCA1 agonists (TSAAgs) as Alzheimer's Disease (AD) drug candidates with multifactorial therapeutic potential. We are utilizing medicinal chemistry approaches to synthesize novel lead TSAAgs based on chemotypes that have been identified and validated in a high-throughput screen. Lead TSAAgs will undergo extensive evaluation in vitro, followed by in vivo testing in healthy mice to establish pharmacodynamic and pharmacokinetic profiles and in two preclinical disease models to assess their potential as AD therapeutics for progression into human clinical trials. Greg Thatcher, Ph.D. lewando4@uic.edu
Morrissey, Zachery I will be using resting-state functional magnetic resonance imaging (rs-fMRI) to study the connectome changes that occur in transgenic mouse models of Alzheimer's Disease (AD) and neurogenesis. By using molecular biology techniques in conjunction with emerging neuroimaging analysis methods, we can better understand the cellular and neural network mechanisms underlying neurodegeneration. These experiments will give a system-level insight into how brain connectomes are altered as a result of AD, and improve our clinical understanding of how cognition improves as a result of environmental enrichment and neurogenesis. Alex Leow, MD/Ph.D. and Orly Lazarov, Ph.D. zmorri4@uic.edu
Bonds, Jacqueline There are several risk factors that contribute to the development of Alzheimer's disease (AD), including insulin resistance and type 2 diabetes (T2D). According to data collected from the Mayo Clinic Alzheimer's Disease Registry, more than 80% of AD cases also present with either T2D or an impaired glucose metabolism disorder. Unfortunately, the mechanisms underlying the link between these two diseases is complex and very poorly understood. This project aims to clarify how deficits in caveolin-1 expression in the brain causes AD-related neuropathology and compromised neurogenesis. Orly Lazarov, Ph.D. and Jacob Haus, Ph.D. jbonds3@uic.edu
Lee, Sue Recent reports have linked traumatic brain injury (TBI) ranging from sport athlete's concussions to soldier blast impacts to earlier onset dementia. Still the link between mild trauma and its role in the ability to deplete a person's "cognitive reserve" as they age leading to dementia is still unknown. The proposed research seeks to 1) characterize a novel mouse model of aging, Aldh2-/-, induced with either single or repetitive mTBI, 2) identify and visualize lipid distribution changes on brain slices of these mice with MALDI imaging mass spectrometry, and 3) utilize computational and MRI neuroimaging techniques to identify mechanisms that may lead to identification of underlying mechanisms or early biomarkers that lead to increased risk of dementia. We hypothesize that by better understanding the long-term negative consequences of TBI from different perspectives will allow us to develop treatments for ADRD with prior mTBI. Greg Thatcher, Ph.D. and Stephanie Cologma, Ph.D. suelee1@uic.edu