Medical Neuroscience Department Theses and Dissertations
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Item Sex-Differences in Early-Onset Alzheimer's Disease(2026-01) Nemes, Sára; Yoder, Karmen; Gao, Sue; Hammers, Dustin; Risacher, Shannon; Truitt, William; Apostolova, LianaBackground: Prior research in Alzheimer’s disease (AD) suggests female sex is associated with increased disease risk and pathology burden, but this has not been examined in Early-onset AD (EOAD; onset <65). Using data from the Longitudinal Early-Onset Alzheimer’s Disease Study (LEADS), we examined sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of pathological burden. Methods: Chapter 2 analyses included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 early-onset non-AD (EOnonAD) LEADS participants. Each diagnostic group was stratified by sex and then by APOE ε4 carrier status. Imaging biomarkers were compared across strata, and voxel-wise multiple linear regressions generated statistical maps of gray matter density, amyloid, and tau PET burden. Chapter 3 analyses evaluated the impact of sex and APOE ε4 on plasma and cerebrospinal fluid (CSF) AD biomarkers. We included 201 EOAD, 64 EOnonAD, and 86 CN participants with plasma data; of these, 100 EOAD, 35 EOnonAD, and 38 CN also had CSF data. Participants were stratified by sex and APOE ε4 genotype. Demographics and biomarker differences were compared using ANOVA within diagnostic groups, and ANCOVA models controlled for age and education. Results: In imaging analyses, EOAD females showed greater amyloid and tau PET burdens than males. EOAD female APOE ε4 non-carriers exhibited greater amyloid burden and gray matter atrophy than female ε4 carriers; EOnonAD female non-carriers also showed greater atrophy. EOAD women had higher plasma NfL and GFAP, with comparable Aβ42/40 and pTau231 levels relative to men. In CSF, EOAD women had higher neurogranin, tTau, pTau181, and VILIP1. EOnonAD women had higher plasma GFAP. In CN participants, women showed higher CSF SNAP25, whereas men showed a trend toward higher plasma pTau231. APOE ε4 status did not influence plasma or CSF biomarker levels in either sex. Conclusion: These analyses show that female sex and APOE ε4 status are associated with greater pathology burden in EOAD. As specific AD fluid biomarkers emerge, understanding sex-based differences across PET, CSF, and plasma measures is critical and supports further study of sex- and APOE-ε4–related variation in biomarker expression and its relevance to EOAD diagnosis and treatment.Item Association of Head Injury with Multimodal Alzheimer's Disease Biomarkers and Genetics(2025-12) Dybing, Kaitlyn Marie; Yoder, Karmen K.; Risacher, Shannon L.; Saykin, Andrew J.; Gao, Sujuan; Wu, Yu-ChienAlzheimer’s disease (AD) affects over 7 million Americans aged 65 and older and is the seventh-leading cause of death in the United States. AD represents a tremendous social and economic burden, but development of prevention and/or curative strategies has been slow. While much attention is focused on potential pharmacological therapies to stop and/or reverse disease progression, there is growing interest in lifestyle modifications that may lower risk for developing AD. One key lifestyle-related factor that is associated with elevated dementia risk, including AD is head injury (HI), also called concussion or traumatic brain injury (TBI). HI is extremely prevalent, with studies estimating as many as one in four Americans have experienced one. HI is even more prevalent in at-risk populations, including military service members and contact sport athletes. However, the mechanism(s) responsible for the link between HI and AD risk are largely unclear. While prior work has linked HI to elevated AD biomarkers, particularly amyloid-β (Aβ) and tau measured using positron emission tomography (PET) and via pathological investigation, the evidence is highly varied and its significance unclear. In this thesis, we utilize multimodal biomarker and genetic tools to investigate potential mechanisms involved in the association of HI with AD risk. Chapter One is a systematic literature review of published studies that assessed whether individuals with HI had higher levels of deposited Aβ and/or tau as indicated by PET scans. Chapter Two is an original research report investigating whether AD fluid biomarkers are altered in participants with HI from the Alzheimer’s Disease Neuroimaging Initiative. Chapter Three presents an original research investigation of tau deposition levels in participants with TBI from the National Alzheimer’s Coordinating Center cohort. Finally, Chapter Four is an exploration of whether genetic risk for AD is associated with more severe concussions and/or poorer concussion recovery in student athletes and military service academy students. The complex relationship between HI and dementia risk is not fully characterized, but this body of work elucidates unique and novel associations of AD biomarkers and genetics with HI.Item Investigation of Electrostatic and Heme-Coordinating Mitochondrial Therapeutics for the Treatment of Spinal Cord Injury(2025-12) Ravenscraft, Baylen; Yoder, Karmen; Liu, Nai-Kui; Truitt, William; Brutkiewicz, Randy; Walker, ChandlerTraumatic spinal cord injury (SCI) is a critical medical issue with high mortality and long-term morbidity. There's increasing emphasis on neuroprotective approaches to address the secondary effects post-injury. Targeting mitochondria, key players in cell survival and death, emerges as a promising approach, especially as the peroxidation of cardiolipin (CL) by cytochrome c (Cyt c) has been identified as a necessary and sufficient step of mitochondria-mediated apoptosis. L254614 (L25) is a molecule known to bind tightly to the region of Cyt c in which CL is peroxidized, but the translation of L25 into living cells remained unexplored. On the other hand, Szeto-Schiller peptide 31 (SS-31), a mitochondria-targeted peptide, has shown potential in various pathologies. However, its exploration in SCI is limited, with inconsistent results in basic locomotor functional recovery at doses of 5mg/kg and early endpoints. It remained uncertain if higher doses would enhance locomotion recovery post-SCI from acute to chronic stages and how SS-31 may affect cardiolipin levels. For the first time, both L25 and SS-31 were evaluated within primary spinal cord neuronal cultures from embryonic day 15 rat embryos. While L25 was found to be a toxicant, SS-31 protected against specific injury models. Protection was determined through assays measuring cell death, viability, caspase activation, and neurite morphology. Following in vitro testing, SS-31 was introduced into an in vivo mouse model of thoracic-level-9 (T-9) moderate (60kdyne) contusive SCI. Acute CL alterations via SCI and SS-31 were measured with lipidomic analysis at 1-day post-SCI. Long-term impacts were assessed between 3-days to 8-weeks post-SCI with various locomotor tests and a histological evaluation of the lesion volume 8-weeks post-SCI. Notably, higher concentrations of SS-31, (100-200uM in vitro and 10mg/kg in vivo), showed remarkable neuroprotection with consistent significance in most assays. This study converges the therapeutic approaches targeting Cyt c-mediated peroxidation of CL, either by the heme-coordinating small molecule approach, or with the electrostatic peptide approach, towards contributing a step forward in the race to cure SCI.Item A Simulative Deep Learning Model of SNP Interactions on Chromosome 19 for Predicting Alzheimer's Disease Risk and Rates of Disease Progression(2025-09) Bae, Jinhyeong; Saykin, Andrew J.; Hammers, Dustin; Nudelman, Kelly N.; Zhao, Yi; Apostolova, Liana G.Background: Understanding Alzheimer’s disease (AD) genetic dynamics is key to unraveling its pathophysiology and advancing precision medicine. Current genetic studies, however, fall short in analyzing epistatic interactions between single nucleotide polymorphisms (SNPs). Here, we introduce a novel capsule network–based deep learning framework designed to model and quantify these complex SNP–SNP interactions on AD risk. Methods: In Chapter 1, we developed a novel deep learning model that can examine epistatic interactions of SNPs. Chromosome 19 genetic data from ADNI and ImaGene were used. Their epistatic impacts on AD development were quantified and the top 35 AD-risk SNPs were identified. In Chapter 2, we explored the clinical utility of the top 35 AD-risk SNPs. We performed computational gene-editing simulations, i.e., substituting each risk allele with its reference counterpart, to estimate how these edits would alter an individual’s Alzheimer’s risk. Further, we correlated each SNP’s quantified impact with the rate of cognitive declines and cerebrospinal fluid proteins changes using regression analysis. Results: The model was successfully trained and mapped genetic dynamics of AD in chromosome 19. Rs561311966 (APOC1) and rs2229918 (ERCC1) emerged as the strongest AD-risk SNPs. Computational gene-editing simulation with rs56131196 reduced the likelihood of AD by 7.9%, converting 36% of predicted AD participants to cognitive unimpaired individuals. Regression analyses using the top 35 SNPs yielded significant associations (p < 0.05) with disease progression, with the strongest correlations observed for executive function decline (adjusted r² = 0.433) and the ratio of amyloid beta over total tau change. (adjusted r² = 0.973). Discussion: Our model provided a comprehensive view of SNP interactions on chromosome 19 underlying Alzheimer’s development in a fully hypothesis free manner. The top 35 risk variants formed clusters in six genes: APOC1, TOMM40, ZNF473, VRK3, ERCC1 and APOC2. Multiple biological and clinical studies demonstrate that variants in these genes contribute to Alzheimer’s pathology, particularly through oxidative stress related mechanisms. We quantified the individual impact of these risk variants, enabling in-silico gene editing simulations and prediction of disease progression. This work has the potential to transform preventive precision medicine.Item Investigating the Role of Lysine Methylation in Neuronal Differentiation(2025-07) Hanquier, Jocelyne Nicole; Yoder, Karmen K.; Cornett, Evan M.; Georgiadis, Millie M.; Baucum, Anthony J. II; Pierchala, Brian A.Neuronal differentiation is a critical process during brain development, and aberration in neuronal differentiation has emerged as a major point of convergence for neurodevelopmental disorders (NDDs). Thus, there is a critical need to understand the molecular mechanisms that regulate neuronal cell differentiation. The reversible post-translational modification lysine methylation has reported regulatory roles in neuronal differentiation. While histone lysine methylation is well-studied, insights into the role of non-histone lysine methylation in differentiation remain limited, partly due to the lack of high-throughput profiling in neuronal models. The enzymes that mediate lysine methylation – lysine methyltransferases (KMTs) and demethylases (KDMs) – are critical for brain development. Over a third of KMTs/KDMs have been associated with NDDs, and haploinsufficiency of a number of these enzymes, including the lysine methyltransferase ASH1L, results in aberrations in neuronal differentiation. The overall objective of this work was to gain mechanistic insight into the regulation of neuronal differentiation by lysine methylation of histone and non-histone proteins. Toward this end, we employed a quantitative proteomics approach (tandem mass tag LC-MS/MS) to profile global changes in lysine methylation across differentiation of human neural progenitor cells into post-mitotic, dopaminergic-like neurons using the Lund human mesencephalic (LUHMES) cell model. We quantified hundreds of lysine methylation events on a range of diverse non-histone proteins of biological and clinical interest. To our knowledge, this is the first report of global profiling of lysine methylation across neuronal differentiation by quantitative mass spectrometry. We also sought to determine the contribution of the lysine methyltransferase activity of the NDD-associated enzyme ASH1L toward regulation of LUHMES differentiation. We found that treatment with AS-99, a small molecule inhibitor against ASH1L KMT activity, resulted in deficiencies in neurite length and branching, supporting a critical role for ASH1L KMT activity in LUHMES differentiation regulation. Using biochemical approaches, we confirmed histone H3K36 as a lysine methylation substrate of ASH1L in vitro, and we elucidated the substrate selectivity of ASH1L. Future work will determine the impact of ASH1L-mediated substrate methylation toward regulation of LUHMES differentiation. Taken together, this work supports a critical role for lysine methylation in the regulation of neuronal differentiation.Item Sex Differences in Risky Decision-Making Neural Processing and Its Link to Problematic Substance Use in Adolescents at Risk for Substance Use Disorders(2025-05) Murray, Olivia Kay; Yoder, Karmen; Hulvershorn, Leslie; Conroy, Susan; Dzemidzic, Mario; Truitt, WilliamBackground: Risky decision-making deficits are associated with substance use risk. However, sex differences in risky decision-making neural processing among adolescents with externalizing disorders (EXT), like ADHD and conduct disorder, have been understudied though EXT youth are at high risk for developing substance use disorders (SUDs), partially due to impaired decision-making. While males with EXT tend to engage in more risky behavior, the neural mechanisms underlying these patterns may differ for EXT females. This dissertation presents two studies exploring 1) sex differences in brain activation during risky decision-making, and 2) how these differences relate to problematic substance use in EXT youth. Method: The first study included 168 adolescents (81 EXT males, 39 EXT females, 33 control males, 15 control females), who completed the Balloon Analogue Risk Task (BART) during a magnetic resonance imaging (MRI) session. The second study utilized 115 drug-naive EXT adolescents (78 males, 37 females) who also completed the BART during an MRI session and were assessed for problematic substance use during longitudinal follow-up. Statistical analyses compared sex and EXT differences in brain activation during risky decision-making and the associated risk of substance use using Cox proportional hazards models, respectively. Results: EXT males showed greater activation in the cingulo-opercular network during risky versus safe choice as that choice became riskier (modulated) compared to EXT females and controls. Greater modulated activation in the right nucleus accumbens (NAc) during risky versus safe choice was associated with less problematic substance use in EXT females, but not in EXT males. Greater unmodulated choice phase activation in the NAc in males and in the subgenual anterior cingulate cortex in females were associated with less problematic substance use. Conclusions: This dissertation highlights significant sex differences in both the neural processing of risky decision-making and its connection to substance use in EXT youth. These findings suggest that proper risk processing in the cingulo-opercular and reward networks may protect against substance use, with distinct patterns in males and females. These results underscore the importance of sex-specific approaches for prevention and intervention in youth at risk for substance misuse.Item Elucidating the Role of Ref-1 in Retinal Neovascularization(2025-05) Hartman, Gabriella D.; Yoder, Karmen K.; Corson, Timothy W.; Kelley, Mark R.; Fishel, Melissa L.; Pattabiraman, PadmanabhanRetinal neovascularization in retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR) impairs vision. Current treatments of intravitreal (IVT) antivascular endothelial growth factor (VEGF) injections are accompanied by high treatment burden and resistance. Also, VEGF alone is not sufficient for induction of neovascularization, suggesting that targeting multiple disease-relevant pathways may increase therapeutic response. Thus, there is a critical need to develop novel therapies that modulate multiple disease-relevant pathways. APE1/Ref-1, a multifunctional protein with both endonuclease (APE1) and redox regulatory activity (Ref-1), activates multiple transcription factors linked to retinal neovascularization. However, the precise molecular mechanisms of Ref-1 in retinal neovascularization remain unclear. To investigate this, I examined the expression of Ref- 1 in two mouse models of retinal neovascularization – the oxygen-induced retinopathy (OIR) and the Vldlr-/- model – and observed elevated Ref-1 expression at sites of neovascularization. Further, I observed heightened expression of Ref-1 in endothelial cells in human PDR tissue compared to normal eyes. Through cell-based and biochemical approaches, I identified that Ref-1 redox activity modulates canonical Wnt signaling, and inhibition of Ref-1 redox activity blocks Wnt signaling activation. I found that Ref-1 redox activity regulates HIF-1a transcriptional activation in hypoxic human retinal endothelial cells. Hypoxia-induced activation of Wnt signaling was regulated by Ref-1, suggesting a dynamic Ref-1-HIF-1a-Wnt signaling axis. Finally, inhibition of Ref-1 redox activity decreased retinal neovascularization and downregulated expression of Wnt- and angiogenesis-related genes at sites of neovascularization in a mouse model of retinal neovascularization. These findings suggest that Ref-1 redox activity promotes ischemic retinal neovascularization via Wnt signaling activation. This study advanced our understanding of Ref-1’s role in neovascular eye diseases, and targeting Ref-1 with a redox inhibitor could offer a novel therapeutic strategy for retinal neovascularization.Item The APOE Pathway as a Modulator of Amyloid Pathology in Alzheimer's Disease Models(2025-03) Tate, Mason Douglas; Baucum, AJ; Kim, Jungsu; Bissel, Stephanie J.; Lasagna Reeves, Cristian A.; Oblak, Adrian L.Alzheimer’s disease (AD) is characterized by the accumulation of beta-amyloid (Aβ) peptides and amyloid plaque deposition. The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for sporadic AD, with apoE protein crucial for brain lipid transport. ATP-binding cassette subfamily A member 1 (ABCA1), another risk gene, loads lipids onto apoE, highlighting the importance of lipid homeostasis in AD. MicroRNA-33 regulates the expression of ABCA1 and apoE lipidation, although its effect on amyloid pathology is unknown. Additionally, apoE variants can modulate AD risk. The apoEε4R251G variant eliminates the increased risk associated with the APOEε4 allele. This variant is located within the lipid binding domain of apoE, however its roles in lipid homeostasis and amyloid pathology remain unexplored. This dissertation investigates the role of apoE in amyloid pathology. We first used microRNA-33 knockout mice within an amyloidosis mouse model to determine if increased ABCA1 and apoE lipidation affect amyloid pathology. We demonstrate that deleting microRNA-33 reduced Aβ levels and plaque deposition. Through our multi-omics approach, we identified that microRNA-33 regulates microglial function, and mechanistically confirmed in vitro that inhibition of microRNA-33 increased microglial migration and Aβ phagocytosis. We next explored if the astrocyte-specific deletion of microRNA-33 could similarly reduce amyloid pathology. While the loss of microRNA-33 in astrocytes increased ABCA1 levels, we did not observe an increase in apoE lipidation. Furthermore, the astrocyte-specific deletion of microRNA-33 did not reduce amyloid pathology to the extent seen in the whole-body knockouts, suggesting a critical role for microglial microRNA-33 or a synergistic effect across cell types. Finally, we investigated if the astrocytic expression of the novel R251G apoE variant modulated apoE lipid pathways and amyloid pathology in an amyloidosis mouse model. We show that apoEε4R251G exhibits increased lipid binding compared to apoEε4. Additionally, the R251G variant reduced levels of Aβ and plaque deposition. Furthermore, astrocytes expressing apoEε4R251G colocalized more around plaques compared to apoEε4 mice, suggesting that astrocytes might be influencing the changes observed in amyloid pathology. Collectively, our results highlight the role of apoE lipid homeostasis in AD and potential therapeutic targets that can modulate apoE function and mitigate amyloid pathology.Item The Role of TREM2 and the Responses Mediated by Galectin-3 During Age-Related Myelin Degeneration(2025-03) McCray, Tyler Jacob; Oblak, Adrian L.; Bissel, Stephanie J.; Lahiri, Debomoy K.; Lamb, Bruce T.; McKinzie, David L.Aging is the greatest known risk factor for various neurodegenerative diseases. Myelin degeneration is an early pathological indicator of these diseases and normal part of aging; albeit, to a lesser extent. Despite this, little is known about how age-related degeneration could contribute to and impact development of neurodegenerative disease. Microglia participate in a variety of white matter events from demyelination to remyelination. The microglial innate immune receptor triggering receptor expressed on myeloid cells 2 (TREM2) has been implicated in regulating (de)myelination. We found in response to demyelination, TREM2 is required for large volumes of myelin debris and during extended periods of phagocytosis. In addition to lysosomal regulation, we showed TREM2 can modify the ER stress response prior to overt myelin debris preventing early microglial dysfunction. We found TREM2 is necessary for remyelination by recruiting reparative glia and mediating signaling that promotes OPC differentiation/maturation. One of the signaling factors involved, the β-galactosidase-binding protein galectin-3 (gal-3), was recently identified as a ligand for TREM2, however little is known about this interaction in the context of aging or neurodegenerative disease. Treating microglia with a pharmacological gal-3 inhibitor, we found overlapping functional deficits with Trem2-deficient microglia during myelin phagocytosis. These shared deficits included impaired myelin uptake, altered lysosomal function, ER stress, and lipid droplet accumulation that were rescued inTrem2-deficient microglia with the addition of recombinant gal-3. RNA-seq analyses revealed common genes and pathways affected that importantly included genes associated with the integrated stress response. Taken together, these data suggest Gal-3 mediates and throttles the TREM2-dependent stress response during age-related myelin degeneration. Further, it provides support for targeting TREM2 function early to augment reparative signaling preventing overt debris accumulation and/or promoting gal-3 to alleviate stress pathways that can lead to premature microglial dysfunction and onset of pathology.Item The Impact of INPP5D on Microglia Response to Tau Pathology in Alzheimer's Disease(2025-02) Soni, Dishaben Miteshkumar; Truitt, William A.; Oblak, Adrian L.; Lasagna-Reeves, Cristian; Bissel, Stephanie J.; Chu, ShaoyouAlzheimer’s Disease (AD), the most prevalent form of dementia, is neuropathologically defined by the extracellular buildup of amyloid-beta (Aβ) plaques, the formation of intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein, and progressive neuronal degeneration, ultimately leading to cognitive decline. Genetic studies have identified immune-related risk genes linked to AD, underscoring the regulatory role of microglia in AD pathogenesis. Among these genes, INPP5D, which is exclusively expressed by microglia in the brain, has been associated with an increased risk for AD. Elevated INPP5D expression in microglia correlates with amyloid-plaque burden in human AD brain tissue, and studies indicate that INPP5D deficiency modulates amyloid pathology, with effects differing by disease stage and model system. While INPP5D modulation has been shown to impact amyloid pathology, its influence on tau pathology remains largely unexplored. This dissertation seeks to illuminate the role of INPP5D in tau pathogenesis. Our initial studies demonstrated a positive correlation between INPP5D expression and tau-seeding activity in human AD brain samples. Likewise, we observed increased INPP5D expression associated with phospho-tau AT8 levels in PS19 mice, indicating a significant link between INPP5D and tau pathology. Building on these findings, we explored the effect of Inpp5d haplodeficiency on tau pathogenesis in PS19 mice, revealing that Inpp5d haplodeficiency recovered motor functions, mitigated tau pathology, lowered proinflammatory cytokine levels and altered microglial morphology without affecting the overall cellular composition. Transcriptomic analysis also showed the upregulation of genes involved in cell migration, immune response, angiogenesis, and wound healing. These results highlight a complex interplay between Inpp5d, tau pathology, and behavioral outcomes, supporting Inpp5d’s involvement in tau pathogenesis. To explore this further, we treated primary microglia isolated from Wildtype, Inpp5d+/-, and Inpp5d-/- mice with recombinant mutant tau-preformed fibrils and insolubletau extracted from PS19 mice brains. Our results revealed increased tau uptake in Inpp5d+/- and Inpp5d-/- microglia, suggesting that Inpp5d modulation enhances tau uptake, potentially influencing disease progression through altered microglial response. While further research is needed to clarify the mechanisms through which INPP5D influences tau pathogenesis, our findings highlight INPP5D as a promising therapeutic target for modulating tau pathology and improving microglial function in AD.