Life Sciences Commons^™

Neuroinflammation Levels Measured By Microglial Cell Activation, Emma G. Whitlock, Linda S. Yasui

Honors Capstones

Neuroinflammation is an inflammatory response in the brain that can be caused by different stressors such as diseases and/or external factors such as traumatic brain injuries. It is important to note duration and intensity of neuroinflammation levels when determining the impacts of these stressors to the brain environment. During neuroinflammation, a type of immune cell that becomes activated in the brain is called microglial cells. Microglial cells play a role in progression of the pathophysiological effects from the brain stressor. Studying changes in microglial cell shape provides evidence of the degree of neuroinflammation in the brain. Researchers can quantify neuroinflammation …

Isolation Of Aged Mouse Primary Microglia As A Model System For Alzheimer’S Disease Research, Michael Landis

Biology Honors Papers

Microglia and their role as the immune cells of the central nervous system are an emerging area of interest within Alzheimer’s research, particularly as they have shown in a benevolent and malevolent cellular context. Models of Alzheimer’s disease are very light in studying microglia, so in this study a model of microglia isolated from aged mice is established in order to study the phagocytic activity and protein expression of microglia in response to Amyloid Beta. The cells were isolated from aged mice and cultured before being used to confirm cellular identity, as well as to measure phagocytic activity. This study …

Complement System In Multiple Sclerosis: Its Role In Disease Course And Potential As A Therapeutic Target, Michael R. Linzey

Dartmouth College Ph.D Dissertations

Multiple sclerosis (MS) is a clinically heterogeneous neurological condition characterized by neuroinflammation and neurodegeneration. Relapsing-remitting MS, defined by inflammatory attacks, is the most common initial form of MS and there are currently 23 FDA-approved treatments for these patients. These therapies work primarily by reducing inflammation in the CNS; they do not work well in progressive disease. Therefore, an unmet medical need exists for effective therapeutic options to treat progressive MS (PMS).

In MS, intrathecal immunoglobulins synthesis (IIgS) correlates with disease progression. My goals for this dissertation were to establish the pathological role of IIgS and identify new potential therapeutic …

Rewired Metabolism In Apoe4 Microglia: Implications For Inflammation And Neurodegeneration, Nicholas A. Devanney

Theses and Dissertations--Physiology

Among the earliest changes to occur in Alzheimer’s disease, metabolic dysfunction and chronic neuroinflammation are now known to be major driving forces in disease progression. The paradigm of ‘immunometabolism’ seeks to bridge these two facets, positing that metabolic transformations are indispensable in determining the response of immune cells, such as microglia – the brain’s resident immune population. Proinflammatory stimulation of microglia leads to a shift away from mitochondrial respiration towards a dramatic upregulation of the glycolysis pathway for energy production. This glycolytic burst provides microglia with a rapid supply of ATP, but comes at a cost, as utilizing glucose to …

The Role Of Dha In The Impact Of Trem2 On Microglia Activation And Alzheimer’S Disease, Michael A. Palmieri Iii

Seton Hall University Dissertations and Theses (ETDs)

Alzheimer’s disease (AD) is a neurological disease that is associated with microglia activation. An important receptor involved in microglia activation is Triggering receptor expressed on myeloid cells 2 (TREM2). Recent studies suggest that docosahexaenoic acid (DHA) could reduce the neuroinflammation that is associated with microglia activation. We hypothesized that when DHA concentration was increased, TREM2 expression would decrease, microglia activity would be inhibited, and a resulting decrease in neuroinflammation would be observed. We examined peer-reviewed journal articles from 2017-2022 that investigated the relationship between TREM2 activation and severity of AD symptoms, the protective properties of DHA against AD, and the …

The Characterization Of Microglia In The Murine Dorsal Telencephalon In Development And Disease, Victoria Neckles

All Dissertations

Microglia are the primary immune cells of the central nervous system and contribute substantially to both development and maintenance of the brain. Negative alterations to microglia often result in detrimental outcomes and significant effort is being made to understand these powerful cells. The goal of this research is to characterize microglia in the developing and diseased murine dorsal telencephalon. In vivo cell labeling and confocal microscopy identified a transient cell type, amoeboid microglia cells (AMCs), that appear to contribute to the development of microglia. Moreover, the spatial distribution and morphological change of microglia was thoroughly characterized during postnatal development. The …

Sex-Specific Effects Of Chaperone And Glial Defenses On Experimental Lewy Body Disease, Tarun Bhatia

Electronic Theses and Dissertations

Lewy body disorders are a group of neurodegenerative conditions characterized by the pathological misfolding and aggregation of the abundant protein, α-synuclein. The most common Lewy body disorders are Parkinson’s disease and dementia with Lewy bodies. Apart from ageing, male sex is a major risk factor for Lewy body disorders, as men are at ~1.5-fold higher risk for these diseases than women. Yet, preclinical studies on Lewy body disorders rarely examine sex as a biological variable, and the mechanisms underlying sex-skewedness in disease risk remain undetermined.

Here, we developed a sex-stratified model of Lewy body disorders by exposing primary neurons harvested …

Investigating The Neuroprotective Effects Of Cannabinoids And Insulin-Like Growth Factors On Glia With Induced Inflammation, Caleb Bloodworth

Honors Theses

Chronic inflammation is a driver of numerous neurodegenerative diseases that reduce quality of life for affected individuals. Non-psychoactive cannabinoids have begun to gain more interest in the world of anti-inflammatory medicine for chronically ill patients. Along with these cannabinoids, insulin-like growth factor-1 has been examined for its association with downregulation of inflammation. Our research aimed to investigate how neuroglia are affected by treatment with cannabinoids or IGF-1 in the face of inflammation from HIV-1 protein, Tat, or lipopolysaccharide (LPS). Preliminary studies in our laboratory showed that neither cannabinoids or IGF-1 treatment altered astrocyte morphology or overall astrocyte viability under baseline …

Innate Lymphoid Cell Characterization And Ilc2s In Neuroinflammation In Aging And Sex Differences, Alexis Mobley, Alexis S. Mobley

Dissertations & Theses (Open Access)

Aging affects immunologic responses by a global immune system suppression, including dysregulation of cytokine mediators, leading to increased inflammation throughout all systems, termed inflammaging. However, understanding healthy aging mechanisms can bypass this effect. Inflammaging also leads to poor outcomes during brain injury, making immune-targeting therapeutics tantamount to overall brain health and longevity. Moreover, sex affects disease etiology and severity through hormonal and chromosomal sex, as the X chromosome contains most immunology-based genes. Androgens have a generally suppressive effect on the immune system. Additionally, when immune responses are mounted, males are better at CD4+ T cell type (Th1) responses, while females …

Hdac6 Inhibition Reverses Long-Term Doxorubicin-Induced Cognitive Dysfunction By Restoring Microglia Homeostasis, Blake Mcalpin

Dissertations & Theses (Open Access)

One in 8 women in the US will be diagnosed with breast cancer. Currently, doxorubicin is one of the most effective chemotherapies for breast cancer. Unfortunately, up to 60% of survivors report long-term chemotherapy-induced cognitive dysfunction (CICD) characterized by deficits in working memory, processing speed, and executive functioning. Currently, no interventions for CICD have been approved by the US Food and Drug Administration. I show here that a 14-day treatment with a blood-brain barrier permeable histone deacetylase 6 (HDAC6) inhibitor successfully reverses long-term CICD following a therapeutic doxorubicin dosing schedule in female mice, as assessed by the puzzle box test …

Sex Differences In Myelin Deficits And Neuroinflammatory Responses To Adolescent Drinking In Rats, Andrea Silva-Gotay

Doctoral Dissertations

Alcohol binge drinking during adolescence is associated with higher risk of developing alcohol use disorders later in life. Alcohol can lead to decreased white matter volume, myelin damage, and neuroinflammation in animal models of adolescent binge alcohol exposure. These deficits in turn are associated with cognitive disfunctions that are long-lasting and could contribute to alcohol abuse and alcoholism later in life. Importantly, human males are more likely to develop alcohol use disorders than females, thus the mechanisms underlying this might be different between the sexes. Understanding how alcohol impacts the developing adolescent brain can help us identify molecular and cellular …

Application Of Confocal Microscopy To Study The Neural Mechanisms Underlying Insect And Rodent Behavior, Christian Michelle Harris

Theses, Dissertations and Capstones

Posture and walking require support of the body weight, which is thought to be detected by sensory receptors in the legs. Specificity in sensory encoding occurs through the morphological properties of the sense organs (numerical distribution, receptor size) and their physiological response characteristics. These studies focus upon campaniform sensilla, receptors that detect forces as strains in the insect exoskeleton. To study the morphology of campaniform sensilla, the sites of mechanotransduction (cuticular caps) were imaged by light and confocal microscopy in four species (stick insects, cockroaches, blow flies and Drosophila). These data indicate that the gradient (range) of cap sizes may …

Microglia Polarize In Response To Transactive Response Dna-Binding Protein-43 (Tdp-43) And Display Partial Recovery After Removal Of The Stimulus, Alicen Wilcox

Honors Theses

The proper response to protein signals is necessary for a healthy central nervous system (CNS), and protein dysregulation is a feature of neurodegenerative diseases. Transactive response DNA-binding protein-43 (TDP-43) is an intranuclear protein, but mislocalization is associated with amyotrophic lateral sclerosis (ALS). TDP-43 is released into the extracellular space where it is sensed by microglia, the CNS-resident immune cells. Our data and the literature suggest that microglia respond to TDP-43 dysregulation by increasing CNS inflammation. The goal of this study was to determine the impact of TDP-43 on microglial function and the extent to which microglia recovery. To study the …

The Functional And Structural Consequences Of Aberrant Microglial Activity In Major Depressive Disorder, Jasmine D. Cakmak

Electronic Thesis and Dissertation Repository

Major depressive disorder (MDD) is a highly debilitating neuropsychiatric illness which has been linked with increases in both peripheral and central inflammation, as well as with changes in connectivity. Although countless studies have investigated these two topics, the relationship between neuroinflammation and functional/structural connectivity has not been explored. Using [¹⁸F]FEPPA PET imaging, we measured translocator protein-related (TSPO) microglial activity in the subgenual anterior cingulate cortex (sgACC) and insula and confirmed significantly increased [¹⁸F]FEPPA uptake in depressed patients (N=12) compared to healthy controls (N=23). Using a seed-based ROI analysis of fMRI data, we found that patients show …

Alcohol As A Catalyst For Hiv-Associated Neuroinflammation And Tbi-Induced Iron Toxicity, Agnieszka Agas

Dissertations

Alcohol has long been considered an exacerbator of diseases, disorders, and injuries as well as many of the accompanying symptoms. As an alternative approach, this dissertation explores alcohol as a catalyst for two different human disease conditions, human immunodeficiency virus (HIV)-associated neuroinflammation and traumatic brain injury (TBI)-induced iron toxicity. In HIV-1 infection, this dissertation presents a novel anti-viral drug, called Drug-S, for a possible inhibition and treatment of HIV-1 disease progression.

The first aim explores the influence of alcohol with HIV-associated neuroinflammation on macrophage migration across an in vitro model of the blood brain barrier. There is a gap in …

Cognitive Changes Caused By Lps-Induced Neuroinflammation, Nancy De La Torre

Dissertations, Theses, and Capstone Projects

The brain performs cognitive processes finely orchestrated by timely precise action of neurons. Neurons functioning at their highest standard communicate with each other through perfectly functioning synapses. Microglia, as part of the immune system assist synaptic processing and have the ability to affect cognition. Indeed, microglia play a role in cognition. To investigate the link between microglia and cognition we utilized lipopolysaccharide (LPS) to pharmacologically activate microglia. LPS, normally present in the environment on the wall of Gram-negative bacteria is a pharmacological agent used to cause microglia activation in mice. LPS is a typical model to study changes induced by …

Myelin, Cpla2, And Azithromycin: Modulation Of Macrophage Activation In Spinal Cord Injury Inflammation, Timothy J. Kopper

Theses and Dissertations--Physiology

Spinal cord injury (SCI) produces a chronic inflammatory state primarily mediated by macrophages consisting of resident microglia and infiltrating monocytes. These chronically activated SCI macrophages adopt a pro-inflammatory, pathological state that continues to cause additional damage after the initial injury and inhibits recovery. While the roles of macrophages in SCI pathophysiology are well documented, the factors contributing to this maladaptive response are poorly understood. Here, we identify the detrimental effects of myelin debris on macrophage physiology and demonstrate a novel, activation state-dependent role for cytosolic phospholipase-A2 (cPLA₂) in myelin- mediated potentiation of pro-inflammatory macrophage activation. Macrophage- mediated inflammatory …

The Effects Of 17alpha-Hydroxyprogesterone Caproate On The Development Of The Mesocortical Dopamine Pathway And Cognitive Behavior, Melanie Lolier

Legacy Theses & Dissertations (2009 - 2024)

This dissertation examined the complex developmental impact of the clinically relevant synthetic progestin 17α-hydroxyprogesterone caproate (17-OHPC) on medial prefrontal cortex (mPFC) development. In rodents, the effects of 17-OHPC are subtle, but significant. In the Chapter II, we observed that 17-OHPC abolishes sex differences in dopaminergic fiber innervation and alters microglia phenotype in the prelimbic and infralimbic areas by the end of the first postnatal week. In the third chapter, the overall effect of 17-OHPC on the ontogeny of dopaminergic fiber innervation and synaptic bouton density were used to characterize the timing and duration of treatment effects in the mPFC. In …

Microglia Induced Neuroinflammation Through The Nlrp3 Inflammasome Following Blast Traumatic Brain Injury, Daniel Younger

Dissertations

The incidence of traumatic brain injury (TBI) among military personnel have been steadily increasing with modern conflicts. A recent RAND report estimated 320,000 service members, totaling 20% of deployed forces, suffer from TBI. However, of this population roughly 60% have not seen a medical professional specifically for TBI. Unlike the civilian population, the primary cause of TBI for active-duty military personnel is blast exposure. Blasts now account for over 70% of all US military casualties in operation Iraqi Freedom (OIF) and Operation enduring freedom (OEF) and are the major cause of TBI. Among many pathological mechanisms associated with blast TBI, …

The Role Of The Circadian Clock Protein Rev-Erba In Neuroinflammation & Synaptic Health, Percy Griffin

Arts & Sciences Electronic Theses and Dissertations

Circadian rhythms are cycles of physiological activity that are conserved across all of life’s taxa – ranging from cyanobacteria to humans - due to their importance. They are conserved to allow organisms to maximize their capacity to obtain resources in their environment. In mammals, light and dark input into the retina is the strongest synchronizer of circadian rhythms. On the molecular level, this tightly regulated transcriptional-translational feedback loop is orchestrated by proteins with cyclical expression. The loss of these proteins has functional consequences on human health and diseases.

Recently, associations have been made between circadian proteins and a host of …

Axonal Regrowth Of Olfactory Sensory Neurons After Chemical Ablation And Removal Of Axonal Debris By Microglia, Rudy Chapman

Electronic Theses and Dissertations

Olfactory sensory neurons (OSNs) are contained within the olfactory epithelium (OE) and are responsible for detecting odorant molecules in the air. The exposure of OSNs to the external environment is necessary for their function, but it also leaves them exposed to potentially harmful elements and thus results in a high turnover rate. Despite the high turnover, the olfactory sense is maintained throughout life through the division of a population of stem cells that produce new OSNs both during normal turnover and after an injury occurs in the OE. When new OSNs are born, they must extend axons from the OE …

Cytotoxic Analysis Of Old Drugs: New Drugs For Alzheimer’S Disease, Sebastian Yumiseba

Theses and Dissertations

Microglia are the resident immune cells of the CNS and constitute about 10% of all cells in the CNS. They have a vital role in Alzheimer’s pathogenesis as either cytotoxic or neuroprotective. Recent efforts are being put into repurposing drugs to target the microglia to treat Alzheimer’s disease.

Regulation And Function Of Trem2-Dependent Pathways In Neurodegeneration, Wilbur Madison Song

Arts & Sciences Electronic Theses and Dissertations

Carriers of the R47H allele of the microglia-specific lipid receptor TREM2 have a greatly increased risk of developing Alzheimerճ disease. The objective of this dissertation is to develop further mechanistic knowledge about how TREM2 is regulated and how TREM2 mutations affect microglia and neurodegeneration. Using an in vitro reporter assay, we find that several AD risk-associated TREM2 mutations decrease ligand-dependent activation. Using humanized TREM2 mice, we find that in vivo, the R47H mutation leads to reduced microglia activation and response to A_, as well as decreased shedding of soluble TREM2. These results suggest that TREM2 is protective during disease. We …

Microglia And Fractalkine Involvement In Shaping Multimodal Midbrain Circuitry, Cooper A. Brett

Masters Theses, 2020-current

Microglial cells (MGCs) are highly dynamic and have been implicated in shaping discrete neural maps in several systems. MGCs respond to numerous cues in their microenvironment, including a neuronally-expressed chemokine, CX3CL1 (fractalkine). The present study examines microglial and CX3CL1 patterns with regard to the emerging modular-extramodular framework within the lateral cortex of the inferior colliculus (LCIC). The LCIC is a shell region of the auditory midbrain where discrete compartments receive modality-specific connections, whereby somatosensory inputs terminate within modules and auditory inputs target surrounding extramodular zones. A reliable modular marker, glutamic acid decarboxylase (GAD), enables visualization of emerging modular domains in …

Lps, A Tlr-4 Agonist And Viper A Tlr-4 Inhibitor Upregulate Phagocytosis Of Zymosan In Bv2 Cells, Sherouk Alzeory

Dissertations and Theses

Microglia cells are the first line of innate immunity defense in the central nervous system (CNS). They play a critical role in maintaining CNS homeostasis by having an active but yet balanced phagocytic activity. However, in various CNS related diseases, microglia cells have been shown to malfunction. In Alzheimer's Disease (AD), hyperactive microglia with impaired phagocytic activity is the main hallmark of this disease, along with the accumulation of amyloid-beta aggregates. Additionally, emerging new studies have suggested a fungal infection etiology to AD, specifically in relation to Candida albicans (C.albicans). Thus, understanding the mechanism of fungal clearance in the …

Regulation Of Neuroinflammation After Ischemic Stroke By Astroglial Endothelin Receptor Type-B Signaling, John Mcinnis

Graduate College Dissertations and Theses

A large body of neuroscientific research has focused on reactive gliosis and glial scar formation because these are among the most prominent features of the cellular response to central nervous system (CNS) injury. Despite much progress in our understanding, controversy remains regarding the relative balance between the protective nature of the astroglial scar and its anti-regenerative features. Recent work suggests that astrocytes are heterogeneous in their resting state and in their reactivity. In traumatic injuries such as stroke and spinal cord injury, proliferative reactive astrocytes protect CNS tissue. By contrast, under neuroinflammatory and/or neurodegenerative conditions, neurotoxic astrocyte phenotypes may contribute …

The Immunological Response To Chronic Stress In Obese Mice, Matthew Corey Parsley

Graduate Theses, Dissertations, and Problem Reports

Obesity and psychological stress are major risk factors for cardiovascular disease and have a positive correlation with vascular dysfunction. This functional deficit has been linked to a pro-inflammatory milieu, exacerbated by an upregulation of pro-inflammatory cytokines. Febuxostat, a xanthine oxidase inhibitor, has been shown to rescue vascular impairment in these models. The purpose of this study was to examine the individual and combined effects of obesity and chronic stress on neuroimmune cell populations, and assess if febuxostat is able mediate immune alterations.

Male mice (n=48) were assigned into either normal chow (lean) and high-fat diet (obese) groups. The lean animals …

The Effects Of A High-Fat Diet On The Brain; A Meta-Analysis Of Microglia In The Hypothalamus, Emily Karabeika

Regis University Student Publications (comprehensive collection)

The typical ‘Western Diet’ includes a diet high in fats and sugars. This thesis explores the problems that this type of diet could have on the brain. A meta-analysis was conducted to show activated microglia count in the hypothalamus of mice after a high-fat diet. The results showed a large effect size with the included studies, showing that a high fat diet significantly increases microglia count across studies. Increased activated microglia leads to chronic inflammation in the hypothalamus, which is linked to metabolic problems like insulin resistance, leptin resistance and glucose intolerance.

Role Of Astrocyte-Derived Extracellular Vesicles In Neuroinflammation Mediated By Drug Abuse, Ke Liao

Theses & Dissertations

Neuronal damage and neuroinflammation is a hallmark feature of HIV-associated neurological disorders (HANDs). Opioids abuse accelerates the incidence and progression of HAND; however, the mechanisms underlying the potentiation of neuropathogenesis by these drugs remain elusive. Extracellular vesicles (EVs) are essential conduits in HIV and drug abuse-mediated synaptodendritic injury and neuroinflammation. Findings from our group have demonstrated that astrocyte-derived EV (ADEV)-miRNA-29b mediates HIV Tat and morphine-induced neuronal injury, thus underscoring the importance of such interactions in NeuroHIV.

Besides, HIV Tat and morphine-mediated synaptodendritic injury via ADEVs, we are also interested in whether ADEVs contributes to neuroinflammation. Microglia are critical players in …

Cyclophilin A Enhances Hiv-1 Reverse Transcription In Human Microglial Cells, Zachary Michael Ingram

MSU Graduate Theses

Parenchymal microglia represent a susceptible cell type to HIV infection and contribute to HIV Associated Neurocognitive Disorders (HAND). Currently, HIV host-protein interactions in microglia are understudied, but relevant to the design of antiviral drugs. HIV replication events rely on host and viral proteins to evade an immune response while improve replication success. Post-fusion the HIV capsid is released into the cytoplasm and begins trafficking towards the nucleus. During transit viral RNA is transcribed to DNA through reverse transcription (RT). In addition, the HIV capsid that protects the reverse transcription complex disassembles in a step termed uncoating. Once the pre-integration complex …