Browsing by Author "Sontheimer, Harald W."

Now showing 1 - 5 of 5
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    Astrocyte and vascular changes contribute to Alzheimer's disease
    Li, Jiangtao (Virginia Tech, 2024-12-19)
    Alzheimer's disease (AD), the most prevalent age-related neurodegenerative disorder, is defined by the pathological accumulation of amyloid-β (Aβ) peptides, neurofibrillary tangles (NFTs), neuronal loss, and the activation of astrocytes and microglia. One of the early indicators of AD is a global reduction in cerebral blood flow (CBF), which precedes significant plaque formation and cognitive decline. This persistent decrease in CBF, along with diminished oxygen and glucose delivery to the brain, is thought to contribute to neurodegeneration, although the underlying mechanisms remain unclear. Astrocytes, critical regulators of both Aβ clearance and CBF, have garnered increasing attention in AD research. Astrocytes, one of the most abundant cell types in the central nervous system, play a vital role in maintaining overall brain health and function. In AD, astrocytes express key AD-related genes, including APP, PSEN1, PSEN2, and APOE. While astrocyte gene expression alterations have been observed, the relationship between these transcriptomic changes, protein expression, and cellular function requires further investigation. This dissertation examines astrocyte and vascular changes in AD using a well-described preclinical AD mouse model: hAPPJ20 mice. First, a multi-omics analysis of cortical astrocyte gene and protein expression was conducted at 3, 6, 12, and 18 months in female J20 and wild-type (WT) mice, revealing significant gene and protein expression differences linked to normal aging and AD progression. Several overlapping gene-protein pairs were identified as potential biomarkers for AD treatment and diagnosis. Gene Ontology analysis highlighted enriched pathways related to inflammation, disrupted metabolism, and vascular dysfunction starting at 6 months. Additionally, pathway analysis revealed apoptotic pathways were enriched in astrocytes isolated from diseased tissue. Further analysis revealed for the first time that astrocytes significantly decline by 12 months in the cortex and hippocampus of J20 AD-disease mice. Nest, we explored vascular network remodeling and amyloid-β (Aβ) accumulation in this same model. In male J20 mice, 40% of the total pial arterial Aβ accumulation was found in the meningeal vascular network by 12 months, while females showed around 20%. Aβ deposition was associated with increased vessel diameter and tortuosity of pial collateral vessels. AD mice also exhibited reduced blood flow in the cortical meningeal arteries and significant enlargement of pial collateral vessels compared to wild-type mice.
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    The gut-brain axis in seizure susceptibility: A role for microbial metabolite S-equol
    Bouslog, Allison Faye (Virginia Tech, 2021-05-26)
    Epilepsy is a complex, chronic neurological disorder with diverse underlying etiologies characterized by the spontaneous occurrence of seizures. Epilepsy affects all ages from neonates to elderly adults, with the most recent CDC estimates stating that ~3 million adults and over 400,000 children are currently suffering from active epilepsy in the U.S. alone. In adults, the leading cause of epilepsy worldwide in central nervous system (CNS) infection, while in neonates the most common cause of seizures is hypoxic/ischemic encephalopathy (HIE). However, in both adults and neonates, current antiepileptic drugs (AEDs) are ineffective in 30-50% of patients, despite the availability of over 20 FDA approved AEDs with diverse molecular targets. This disparity highlights a critical need for novel therapeutics in seizure-susceptibility and epilepsy. The microbes that inhabit gut mucosal surfaces, termed the gut microbiota, have been increasingly implicated in the pathology of neurological diseases including epilepsy. This gut-brain axis is an intriguing therapeutic target in epilepsy as gut microbes can affect the CNS through multiple mechanisms including vagus nerve signaling, immune-gut interactions, and through production of microbial-metabolites including neurotransmitters, short chain fatty acids (SCFAs), lactate, vitamins, and S-equol. Furthermore, the gut microbiota is crucial for neurodevelopment, indicating that the gut-brain axis may be involved in pediatric seizure-susceptibility. This dissertation reviews current evidence on the role of gut metabolites in seizure-susceptibility in epilepsy, highlighting the microbial-derived metabolite S-equol as a potential novel AED. We then evaluate gut microbiome alterations in the Theiler's murine encephalomyelitis virus (TMEV) adult mouse model of CNS infection-induced seizures and find decreases in S-equol-producing bacteria in the gut microbiomes of TMEV-infected mice with seizure phenotypes. We characterize the effect of exogenous S-equol on neuronal function in vitro, demonstrating a reduction in neuronal excitation following S-equol exposure. We additionally characterize entorhinal cortex (ECTX) pyramidal neuronal hyperexcitability, and demonstrate the ability of exogenous S-equol to ameliorate CNS-infection-induced ECTX neuronal hyperexcitability ex vivo. Finally, we demonstrate that perinatal and postnatal exposure to antibiotics alters the gut microbiome and increases seizure-susceptibility following HIE exposure in p9/p10 mice, potentially via sex-specific alterations in neuronal function. Together, this dissertation evaluates the gut-brain axis in pediatric and adult mouse models of seizure-susceptibility and identifies the gut metabolite S-equol as a potential target for the treatment of seizures.
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    Mitochondrial Dynamics Alteration in Astrocytes Following Primary Blast-Induced Traumatic Brain Injury
    Guilhaume Correa, Fernanda (Virginia Tech, 2023-01-11)
    Mild blast-induced traumatic brain injury (bTBI) is a modality of injury that has been of major concern considering a large number of military personnel exposed to the blast wave from explosives. bTBI results from the propagation of high-pressure static blast forces and their subsequent energy transmission within brain tissue. Current literature presents a neuro-centric approach to the role of mitochondria dynamics dysfunction in bTBI; however, changes in astrocyte-specific mitochondrial dynamics have not been characterized. As a result of fission and fusion, the mitochondrial structure is constantly altering shape to respond to physiological stimuli or stress insults by adapting structure and function, which are intimately connected. Dysregulation of the protein regulator of mitochondrial fission, DRP1, and upregulation in the phosphorylation of DRP1 at the serine 616 site is reported to play a crucial role in astrocytic mitochondrial dysfunction, favoring fission over fusion post-TBI. Astrocytic mitochondria are starting to be recognized to play an essential role in overall brain metabolism, synaptic transmission, and neuron protection. Mitochondria are vulnerable to injury insults leading to the worsening of mitochondrial fission and increased mitochondrial fragmentation. In this study, a combination of in vitro and in vivo bTBI models were used to examine the effect of blast on astrocytic mitochondrial dynamics. Acute differential remodeling of the astrocytic mitochondrial network was observed, accompanied by an acute (4hr) and sub-acute (7 days) activation of the GTP-protein DRP1. Further, results showed a time-dependent reactive astrocyte phenotype transition in the rat hippocampus. This discovery can lead to innovative therapeutics targets to help prevent secondary injury cascades that involve mitochondria dysfunction.
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    Modulation of System xc- Mediated Glutamate Release in Glioblastoma Multiforme via the Extracellular Matrix: The Agony and the Xctasy
    Martin, Joelle Dominique (Virginia Tech, 2021-06-21)
    Glioblastoma Multiforme (GBM) is the most common and malignant form of adult brain cancer, with 95% of patients succumbing to the disease within 5 years of diagnosis. An important contributing factor to this poor prognosis is upregulation of the transmembrane protein system xc- (SXC) found on GBM cells. Approximately 50% of GBM patients have tumors with upregulated levels of SXC, and these patients experience faster disease progression than patients with tumors expressing moderate levels of SXC. SXC is a sodium-independent antiporter and is comprised of a light chain catalytic subunit (xCT) bound to a heavy chain regulatory subunit (4f2hc/CD98) via a disulfide bond. The xCT subunit is responsible for the equimolar exchange of extracellular cystine for intracellular glutamate. Clinical studies have shown areas immediately surrounding the tumor, known as the peritumoral region, reach glutamate concentrations over 100 times that of the normal brain, creating an excitotoxic environment in which neurons cannot survive. In addition to neuronal excitotoxicity, excess glutamate release has also been shown to promote GBM cell invasion, as well as contributing to the clinical presentation of seizures in patients. Moreover, cystine is a component of the antioxidant glutathione, which confers protection to the cells from alkylating therapeutics such as temozolomide (TMZ). In an effort to identify novel targets that regulate SXC function, I investigated the relationship between SXC and two signaling molecules known to promote GBM progression: CD44 and the epidermal growth factor receptor (EGFR). I experimentally manipulated the CD44-hyaluronic acid (HA) interaction and EGFR to determine if these two signaling molecules were involved in regulating SXC expression and function in two patient-derived GBM cell lines. Experimental data led me to conclude that the tumorigenic potential conferred to GBM cells by CD44 is not related to an interaction with SXC. However, I found that knocking down EGFR led to a significant reduction in SXC expression. These findings are important to the field, as combinatorial therapies become more actively pursued in clinical trials. Inhibition of EGFR may provide quality of life benefits to patients who suffer from tumor-associated epilepsy through downregulating xCT-mediated glutamate release.
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    Multimaterial multifunctional fibers for biomedical applications
    Jiang, Shan (Virginia Tech, 2021-06-08)
    The aim of my Ph.D. thesis is to summarize my research on the development of multimateiral multifunctional fibers for bio-related application, mainly in the fields of neural interfacing and bioimpedance sensing. Understanding the cytoarchitecture and wiring of the brain requires improved methods to record and stimulate large groups of neurons with cellular specificity. This requires the development of improved miniaturized neural interfaces that integrate into brain tissue without altering its properties. Despite the advancement of the existing neural interface technologies such as microwires, silicon-based multielectrode arrays, and electrode arrays with flexible substrates, the physical properties of these devices limit their access to one, small brain region with single implantation. Beyond neural interfacing, extracting molecular information is crucial for understanding many neurological diseases and disorders. The most adapted methods are fast scan cyclic voltammetry and microdialysis. However, both have some limitations such as offline sensing or lack of selectivity. Furthermore, by concentrating optical fields at the nanoscale, plasmonic nanostructures can serve as optical nanoantennas to achieve ultrasensitive bio-/chemical sensing. But due to the limitation of the sensing mechanism, it is hard to perform the plasmonic sensing in live animals. Moreover, the relatively poor electrical performance of the electrode materials that can be utilized in the thermal drawing process limits the function of the fiber in other types of biomedical application, such as deep brain stimulation and electrochemical sensing. For example, the large inherent electrical resistance of the electrode material will significantly interference the electrical impedance result while the main purpose of this kind of study is to explore the frequency-dependent electrical properties of the tested subjects. To overcome above difficulties This thesis introduces broad application of multimaterial multiplexed fibers in biomedical areas. I first describe the development and application of spatially expandable multifunctional fiber-based probes for mapping and modulating brain activities across distant regions in the deep brain (Chapter 2). Secondly, I present the flexible nano-optoelectrodes integrated multifunctional fiber probes that can have hybrid optical-electrical sensing multimodalities, including optical refractive-index sensing, surface-enhanced Raman spectroscopy, and electrophysiological recording (Chapter 3). Thirdly, I demonstrate that hollow multifunctional fibers enable in-line impedimetric sensing of bioink composition and exhibit selectivity for real-time classification of cell type, viability, and state of differentiation during bioprinting (Chapter 4). The same device allows for local delivery of immune checkpoint blockade antibodies and for monitoring of clinical outcomes by tumor impedance measurement over the course of weeks with the photodynamic therapy option to enhance anti-tumor immunity and prolong intratumoral drug retention (Chapter 5). An overview future work has been summarized (Chapter 6).