Medicine and Health Sciences Commons^™

Role Of Chronic Stress-Induced Neuroinflammation In Rodent Locus Coeruleus Physiology And Anxiety-Like Behaviors, Arthur Anthony Alfonso Reyes

Graduate School of Biomedical Sciences Theses and Dissertations

The locus coeruleus (LC), the primary site of brain norepinephrine (NE), is a key anatomical brain region implicated in the stress response. Stress is a neuroendocrine physiologic response to a stressor that promotes organism survival through adaptive change and restoration of homeostasis. The central stress response, which drives behavioral and physiological change, is primarily mediated by activating the hypothalamic-pituitary-adrenal (HPA) axis. While advantageous in the short term, chronic stress exposure can lead to HPA axis and LC dysregulation, which are thought to contribute to the etiology of anxiety disorders. Previous studies demonstrate the effects of acute stress in increasing LC …

Bioinformatic Analysis Predicts Microglial Dysfunction In Murine Aging, Amadu Idrisa Jalloh

USF Tampa Graduate Theses and Dissertations

Age-related disease is a growing concern as the global geriatric population increases. Neurodegenerative diseases scale unfavorably in prevalence with aging and inflict disastrous consequences to human health and well-being. These disorders are challenging to investigate because they arise from complex molecular origins. The neuroimmune system is a common factor among these diseases and microglia play an important role in maintaining homeostasis in the central nervous system. Aging progressively impairs microglia by decreasing their ability to adapt and respond to noxious environmental stimuli or injury. Microglial dysfunction aggravates neurodegenerative pathology when microglia are unable to regulate neuroinflammation effectively. We investigated aging …

Proteostasis & Neuroinflammation In Alzheimer's Disease, Christa C. Huber

Dissertations and Theses

Alzheimer’s Disease (AD) is a devastating disorder with no disease-modifying agent that stops or reverses the progression of the disease. Exosomes, 50 – 150 nanometers in diameter extracellular vesicles, play a role in intracellular communication and are currently being explored as a therapeutic agent in various diseases. In addition, exosomes possess favorable characteristics as a therapy; however, their low yield following isolation hinders their ability as a therapeutic agent. We exposed neuroprogenitor cells to heat shock (HS) before exosomes were isolated to explore the possibility of increasing exosome secretion. HS-derived exosomes exhibit significantly increased concentration and diameter compared to non-heat …

On The Roles Of Trait Anxiety And Toll Like Receptor 4 In Amphetamine Sensitization In Adolescent Male Rats, Corey A. Calhoun

Graduate Doctoral Dissertations

Mammalian adolescence can be a difficult transition from childhood to adulthood, where increases in impulsivity and novelty- and risk-seeking are combined with heightened affect and elevated sensitivity to stress. Indeed, during adolescence, first drug use patterns emerge and in the continental United States, increasing misuse of amphetamines has been observed in adolescent youth. Myriad neural mechanisms underlie this shift in adolescence, including the dynamic remodeling of the mesocorticolimbic (MCL) pathway. Repeated drug administration affects neuroimmune substrates within the MCL circuit including toll-like receptor 4 (TLR4)Advances in addiction neuroscience indicate that drugs of abuse activate neural TLR4 and implicate glial TLR4 …

Impact Of Interleukin-34 On The Promotion Of Bone Osteolysis And Neuroinflammation In Experimental Models Of Alzheimer’S Disease, Anny Ho

All HCAS Student Capstones, Theses, and Dissertations

Alzheimer’s disease (AD) is a growing health concern and is the most common type of dementia worldwide. Emerging evidence indicates that aggregated amyloid-beta (Aβ) peptides, one of the hallmark features of AD neuropathology, can increase RANKL-mediated osteoclast activity leading to the prevalence and severity of inflammatory osteolysis, e.g., osteoporosis and periodontal bone loss. Conversely, osteolytic lesions are associated with increased risk of dementia diagnosis indicating that there is a direct link between dementia and inflammatory osteolysis. It was demonstrated that the neuronal cells primarily produce interleukin-34 (IL-34) and microglia, macrophages, and osteoclast precursors express colony-stimulating factor 1 receptor (CSF-1R), a …

Immunomodulatory Roles Of The Lysosomal Sialidase Neuraminidase 1, Leigh Ellen Fremuth

Theses and Dissertations (ETD)

Background Sialic acids are key sugar moieties located at the non-reducing terminals of glycan chains on glycoproteins and glycolipids. By virtue of their location, they influence the functions and biochemical properties of the macromolecules they are bound to. Removal of sialic acids in mammalian cells is carried out by four sialidases, which are differentially expressed and localized in distinct subcellular compartments. Neuraminidase 1 (NEU1), the most abundant and ubiquitous of the four sialidases, functions primarily in the acidic environment of the lysosomes, but can hydrolyze substrates at the plasma membrane, at least in certain cell types. The enzyme initiates the …

Evaluating The Role Of Mmp9 In Hyperhomocysteinemia Induced Cerebrovascular Pathology, Alexandria Linton

Theses and Dissertations--Neuroscience

Vascular contributions to cognitive impairment and dementia (VCID) is one of the leading causes of dementia, along with Alzheimer’s disease (AD), and often manifests as a comorbidity of AD. Elevated plasma homocysteine, known as hyperhomocysteinemia (HHcy), is a risk factor for VCID; however, the mechanism underlying the connection between HHcy and development of VCID pathology remains elusive. Understanding this mechanism would reveal novel therapeutic targets with the potential to be disease modifying, which are a critical need for a disease that lacks any approved treatment. Previous studies from our lab have strongly associated neuroinflammation and blood brain barrier (BBB) dysregulation …

Uncovering The Role Of Apoe4 On Alzheimer’S Disease-Related Neuroinflammation, Courtney Marie Kloske

Theses and Dissertations--Physiology

Alzheimer’s disease (AD) is the most common neurodegenerative disease and is characterized by two hallmark pathologies: amyloid-beta plaques (Ab plaques) and hyperphosphorylated, aggregated tau tangles. These pathologies are typically accompanied by the presence of neuroinflammation which is primarily mediated by microglia. Interestingly, several genetic risk factors that increase the risk of AD also have direct impacts on neuroinflammation. Of interest, Apolipoprotein E (ApoE) is the largest genetic risk factor for AD. ApoE has three isoforms- E4 confers an increased risk for AD, E3 is considered the “control” phenotype, and E2 is protective against AD. E4 plays a role in virtually …

Cns Antigen Presentation And Immune Cell Infiltration In An Α-Syn Model Of Parkinson Disease, Aubrey Michelle Schonhoff

All ETDs from UAB

Parkinson disease (PD) is a neurodegenerative movement disorder that is characterized by aggregated alpha-synuclein (a-syn), loss of dopaminergic neurons, and neuroinflammation. This neuroinflammation includes the activation of immune cells that reside in the CNS, such as microglia and border associated macrophages (BAMs), in addition to the infiltration of peripheral leukocytes and increased cytokine and chemokine production. Because of the involvement of both the innate and adaptive immune systems, we sought to investigate their interaction through antigen presentation and determine what role this played in disease progression. Using an a-syn based mouse model of PD, our studies have provided evidence via …

Janus Kinase 1 Drives Endoplasmic Reticulum Stress-Induced Transcriptional Reprogramming In Astrocytes, Savannah Graham Sims

Graduate Theses, Dissertations, and Problem Reports

Neurological and neurodegenerative diseases are heterogenous and devastating diseases with limited therapeutic options and no cures. The broad, long-term goal of this project was to elucidate therapeutic targets for neurodegenerative conditions that attenuate damaging inflammation while leaving the beneficial immune response intact and avoiding broad immunosuppression. Inflammation and the accumulation of misfolded proteins are associated with a wide variety of neurological diseases. Here, we have examined how the accumulation of misfolded proteins shapes inflammatory signaling in the glial cell population astrocytes. Astrocytes are the most populous cell in the central nervous system (CNS) and provide physical and trophic support to …

Immune Modulation As A Therapeutic Target In An Α-Synuclein Model Of Parkinson’S Disease, Meena Subhashini Subbarayan

USF Tampa Graduate Theses and Dissertations

Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting about 1.5 million people in the United States with more than 60,000 people diagnosed each year. It is classically characterized by four major symptoms: tremor, postural instability, stiffness in joints, and slow movement (bradykinesia). Pathologically PD is characterized by up to 70% loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) of midbrain and accumulation of presynaptic protein called α-synuclein (α-syn) within dopaminergic neurons that extend to the striatum. This disrupts the nigrostriatal pathway leading to the motor symptoms seen in PD patients. Microglia, the innate immune cells …

An Approach For The In-Vivo Characterization Of Brain And Heart Inflammation In Duchenne Muscular Dystrophy, Joanne Tang

Electronic Thesis and Dissertation Repository

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder caused by dystrophin loss—notably within muscles and CNS neurons. DMD presents as cognitive weakness, progressive skeletal and cardiac muscle degeneration until pre-mature death from cardiac or respiratory failure. Innovative therapies improved life expectancy, but this is accompanied by increased late-onset heart failure and emergent cognitive degeneration. Thus, there is an increasing need to both better understand and track disease pathophysiology in the dystrophic heart and brain prior to onset of severe degenerative symptoms. Chronic inflammation is strongly associated with skeletal and cardiac muscle degeneration, however chronic neuroinflammation’s role is largely unknown in …

Neurite Orientation Dispersion And Density Imaging In A Rodent Model Of Mild Traumatic Brain Injury, Patrick Mccunn

Electronic Thesis and Dissertation Repository

Mild traumatic brain injury (mTBI) has become a focal point within the medical community due to its increased prevalence in recent years. Unfortunately, there is currently no neuroimaging technique able to accurately diagnose and monitor mTBI in-vivo. One technique that has shown great promise is neurite orientation dispersion and density imaging (NODDI). NODDI is a diffusion MRI (dMRI) technique used to characterize microstructural complexity through the compartmental modelling of neural water fractions into Intra-neurite, Extra-neurite and CSF volume fractions. The overreaching theme of this thesis was to validate NODDI in a preclinical setting to then be applied to imaging …

The Role Of Suppressor Of Cytokine Signaling 3 In Neuroinflammatory Disease, Zhaoqi Yan

All ETDs from UAB

The Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) pathway plays a critical role in cytokine-mediated responses in both innate and adaptive immunity, and dysregulation of the JAK/STAT pathway is linked to many inflammatory disorders. Multiple Sclerosis (MS) is an inflammatory demyelinating disease that affects the central nervous system, and both innate and adaptive immunity are involved in disease progression. STAT3 signaling is critically involved in MS pathology and is negatively regulated by Suppressor Of Cytokine Signaling 3 (SOCS3). Both increased STAT3 activation and reduced SOCS3 expression are observed in immune cells from patients with MS. Although the role of …

The Role Of Apolipoprotein E In Regulating Tau Pathogenesis And Neurodegeneration In A Tauopathy Mouse Model, Yang Shi

Arts & Sciences Electronic Theses and Dissertations

APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). APOE4 increases brain amyloid-β (Aβ) pathology relative to other APOE isoforms. However, whether APOE independently influences tau pathology, the other pathological hallmark of AD and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human APOE knock in (KI) or APOE knockout (KO) background, we show that the presence of human APOE, regardless of APOE isoforms, leads to various degrees of brain atrophy in 9-month old P301S mice, whereas APOE ablation strongly protects against neurodegeneration. In particular, P301S/E4 mice develop …

Proteolysis Of Cx3cl1 Impacts Cx3cr1 Signaling And Therapeutic Benefits In A Tauopathy Model, Dylan John Finneran

USF Tampa Graduate Theses and Dissertations

Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder and the most common form of dementia. The hallmark pathologies of AD are extracellular aggregates of amyloid-beta, intracellular aggregates of microtubule associated protein tau and increased neuroinflammation. Current therapeutics offer only symptomatic relief and clinical trials investigating therapeutic benefits of non-steroidal anti-inflammatory drugs have yielded no positive results. Therefore, recent work has focused on immunomodulators, such as CD200 and fractalkine, as potential therapeutic targets for AD.

Fractalkine (CX3CL1; FKN) is expressed as a transmembrane protein with an N-terminal chemokine domain followed by a long, mucin-like stalk. FKN can signal as a membrane-bound …

Investigations Of Interleukin-1 Alpha As A Novel Stroke Therapy In Experimental Ischemic Stroke, Kathleen Elizabeth Salmeron

Theses and Dissertations--Neuroscience

Stroke is a leading cause of death and disability worldwide. Although rapid recognition and prompt treatment have dropped mortality rates, most stroke survivors are left with permanent disability. Approximately 87% of all strokes result from the thromboembolic occlusion of the cerebrovasculature (ischemic strokes). Potential stroke therapeutics have included anti-inflammatory drugs, as well as many other targets with the goal of mitigating the acute and chronic inflammatory responses typically seen in an ischemic stroke. While these approaches have had great success in preclinical studies, their clinical translation has been less successful. Master inflammatory cytokines, such as IL-1, are of particular interest. …

Mass-Spectrometry Based Proteomics Of Age-Related Changes In Murine Microglia, Antwoine Flowers

USF Tampa Graduate Theses and Dissertations

The last century has seen a steady increase in the extension of the average lifespan. This has concomitantly produced higher incidences of age-related chronic degenerative diseases like Alzheimer’s and Parkinson’s diseases. Age is the single greatest risk factor for the development of not just these degenerative conditions but cancer as well. The aged niche undergoes a number of maladaptive changes that allow underlying conditions to present and progress. Exactly which changes, contribute to the progression of which disease is currently an area of intense study. However, these answers often present therapeutic targets for disease prevention. Age is characterized by a …

Neuroinflammation In Alzheimer's Disease And Vascular Cognitive Impairment, Erica M. Weekman

Theses and Dissertations--Physiology

It was once believed that the brain was immunologically privileged with no resident or infiltrating immune cells; however, now it is understood that the cells of the brain are capable of a wide range of inflammatory processes and phenotypes. Inflammation in the brain has been implicated in several disease processes such as Alzheimer’s disease (AD) and vascular cognitive impairment and dementia (VCID); however, the role of inflammation in these two dementias is poorly understood.

When we stimulated a pro-inflammatory phenotype with an adeno-associated viral vector in a transgenic mouse model of AD that develops Aβ plaques, we saw a pro-inflammatory …

The Role Of Hur In Astrocytes In Spinal Cord Injury, Thaddaeus Kwan

All ETDs from UAB

Neuroinflammation is a defining event during the acute phase of spinal cord injury (SCI). The inflammatory cascade is initiated by activated glial cells such as astrocytes and microglia in the milieu of the injured tissue through release of pro-inflammatory cytokines, matrix metalloproteinases, and reactive oxygen species. These soluble factors produce cytotoxicity to neurons and other cells either directly or indirectly by promoting permeabilization of the blood-spinal cord barrier, edema and subsequent ischemia. These factors also serve to recruit and activate additional glia and peripheral immune cells. The mRNAs of many of these soluble factors such as TNFα, IL-1β, CXCL1, and …

Modeling Mild And Repeated Mild Traumatic Brain Injury Induced Functional And Pathophysiological Alterations, Jessica Nicole Nichols

All ETDs from UAB

Mild traumatic brain injury (mTBI) is a major health concern and accounts for over 75% of the 2.5 million brain injuries reported annually in the United States. Afflicted individuals typically experience a broad spectrum of physical, cognitive, and neuropsychological symptoms. Repeated mTBIs (rmTBIs) can further exacerbate these physiological alterations and negatively impact patient quality of life. Currently, there are no therapeutic agents that have successfully navigated clinical trials to be shown efficacious despite mounds of preclinical evidence suggesting to the contrary. This lack of translation exposes the dire need to design, characterize, and implement better and more relevant model systems …

Microglia Orchestrate The Inflammatory Response To Alpha-Synuclein In Parkinson Disease Models, Aaron Thome

All ETDs from UAB

Parkinson disease (PD) is the most common neurodegenerative movement disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and widespread aggregates of the protein alpha-synuclein (α-syn). Increasing evidence points to inflammation as a chief mediator of PD with many of the inflammatory manifestations of human PD cases recapitulated in animal models of PD. We began by examining the inflammatory potential of α-syn fibrils, a newly characterized α-syn conformation that is neurotoxic and prion-like in its endogenous α-syn recruitment and cellular transmission. Our studies provide evidence that the α-syn fibrils evoke a pro-inflammatory response …

Role Of Cerebrovascular Abnormality In Neurodegenerative Disease And Subcortical Ischemic Disease: Ct Perfusion And Pet Imaging, Jun Yang

Electronic Thesis and Dissertation Repository

Clinical studies indicate that about 30% ~ 50% of patients have cognitive impairment after the first or recurrent stroke. Ischemic injury, particularly subcortical lesions, caused by stroke has been demonstrated to further exacerbate cognitive impairment of Alzheimer’s disease (AD) and vascular dementia. However, the mechanisms whereby cerebrovascular abnormalities contribute to neurodegeneration at early stage of disease and eventually to cognitive decline remain unclear. CT perfusion and positron emission tomography (PET) were used to investigate early mechanisms in a rat comorbid model of cerebral ischemia (CI) and β-amyloid (Aβ, a pathological hallmark of AD) toxicity, and in patients with small subcortical …

Analyzing A-Series Gangliosides In Neurons Following Exposure To Glutamate, Dae Hee Park

Electronic Thesis and Dissertation Repository

Neurons within different brain regions have varying levels of vulnerability to external stress and therefore respond differently to injury. A potential reason to explain this may lie within a key lipid class of the cell’s plasma membrane called gangliosides. These glycosphingolipid species have been shown to play various roles in the maintenance of neuronal viability. The purpose of this study is to use electrospray ionization mass spectrometry (ESI-MS) technique and immunohistochemistry to evaluate the temporal changes in the expression profiles of various ganglioside species during the course of neurodegeneration in rat primary cortical neurons exposed to glutamate toxicity. Primary embryonic …

Mechanisms Of Seizure During Pregnancy And Preeclampsia, Abbie Chapman Johnson

Graduate College Dissertations and Theses

Eclampsia is defined as de novo seizure in a woman with the hypertensive complication of pregnancy known as preeclampsia (PE), and is a leading cause of maternal and fetal morbidity and mortality worldwide. The pathogenesis of eclamptic seizure remains unknown, but is considered a form of hypertensive encephalopathy where an acute rise in blood pressure causes loss of cerebral blood flow (CBF) autoregulation and hyperperfusion of the brain that results in vasogenic edema formation and subsequent seizure. However, eclamptic seizure can occur during seemingly uncomplicated pregnancies, in the absence of hypertension and PE, suggesting that normal pregnancy may predispose the …

The Effect Of Acute Lps-Induced Immune Activation And Brain Insulin Signaling Disruption In A Diabetic Model Of Alzheimer's Disease, Andrew Scott Murtishaw

UNLV Theses, Dissertations, Professional Papers, and Capstones

Alzheimer's disease (AD) is a neurodegenerative disorder marked by progressive cognitive impairments and pathological hallmarks that include amyloid plaques, neurofibrillary tangles, and neuronal loss. Several well-known mutations exist that lead to early-onset familial AD (fAD). However, these cases only account for a small percentage of total AD cases. The vast majority of AD cases are sporadic in origin (sAD) and are less clearly influenced by a single mutation but rather some combination of genetic and environmental risk.

The etiology of sAD remains unclear but numerous risk factors have been identified that increase the chance of developing AD. Among these risk …

Implications Of Human Umbilical Cord Blood Cells: An Immunotherapeutic Strategy For Alzheimer's Disease, Donna Darlington

USF Tampa Graduate Theses and Dissertations

ABSTRACT

Alzheimer's disease (AD) is the most common progressive age related dementia and the fourth major cause of mortality in the elderly in the United States. AD is pathologically characterized by deposition of amyloid beta (Aβ) plaques in the brain parenchyma and neurofibrillary tangles (NFTs) within the neuronal soma. While pharmacological targets have been discovered, current strategies for the symptomatic or disease-modifying treatment of AD do not significantly slow or halt the underlying pathological progression of the disease. Consequently, more effective treatment is needed. One possibility for amelioration is using human umbilical cord blood cell (HUCBC) therapy. HUCBCs comprise a …

Quantitative Evaluation Of Microglial Activation And Vascularization In Suicide, Tatiana Pavlovna Schnieder

Dissertations, Theses, and Capstone Projects

Accumulated evidence points to immunological factors in psychiatric disorders. In a variety of chronic neurological disorders, exacerbation is associated with inflammation and a loss of integrity of the blood-brain barrier. Microglia, the principal brain immunological cells in the healthy state, respond to changes in the internal environment of the brain through a sequence of activated states. This study compared microglial phenotypes in the white matter of autopsy brains from 11 suicide victims and 25 subjects who died involuntarily. Both groups included cases with and without major psychiatric disorders, which were determined by PA interviews. Cases were matched for sex, age, …

Microglia Activation In A Rodent Model Of An Alcohol Use Disorder: The Importance Of Phenotype, Initiation, And Duration Of Activation, Simon A. Marshall

Theses and Dissertations--Pharmacy

Chronic ethanol exposure results in neuroadaptations that drive the progression of an alcohol use disorder (AUD). One such driving force is alcohol-induced neurodegeneration. Neuroinflammation has been proposed as a mechanism underlying this damage. Although neuroinflammation is a physiological response to damage, overactivation of its pathways can lead to neurodegeneration. A hallmark indicator of neuroinflammation is microglial activation, but microglial activation is a heterogeneous continuum of phenotypes that can promote or inhibit neuroinflammation. Furthermore acute microglial activation is necessary to restore homeostasis, but prolonged activation can exacerbate damage. The diversity of microglia makes both the level and timecourse of activation vital …

Cytokine Signaling In A Mouse Model Of Parkinson's Disease, Shuwen Cao

All ETDs from UAB

The protein alpha-synuclein (α-SYN), which is found in the Lewy bodies of dopaminergic (DA) neurons in the substantia nigra (SN), has an important role in the pathogenesis of Parkinson's disease (PD). Fcγ receptors (FcγR) are proteins present on the surface of microglia, which bind immunoglobulin G (IgG) and other ligands. Our studies in an AAV-synuclein mouse model of PD showed that over-abundance of α-SYN triggered the expression of NF-κB p65, and led to microglial activation and DA neurodegeneration; however, in mice deficient of gamma chain subunit of the Fc receptors (FcγR-/- mice), α-SYN-induced NF-κB signaling was blocked, while microglial activation …