Molecular and Cellular Neuroscience Commons^™

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 …

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 …

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 …

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 …

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 …

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 …

Brain-Specific And Systemic Inflammatory Response Following Repetitive Concussive Impact In A Mouse Model, So Young Eo

Electronic Thesis and Dissertation Repository

Concussion is the most common form of mild traumatic brain injury (mTBI). TBI resolution is modulated by neuroinflammation, which is augmented by the infiltration of innate immune cells from the circulation. Peripheral, myeloid immune cells not only invade neural tissues but other organs as well causing local inflammation and tissue damage, known as systemic inflammatory response syndrome. Here, I assessed the temporal and anatomical nature of the neural and systemic cellular inflammatory response to repetitive, mTBI in a 3-hit mouse model of concussion. The results showed significant microglial activity, accumulation of peripheral myeloid cells and prominent axonal damage post-injury. The …

Rejuvenation Of The Epigenetic Landscape Of The Aged Brain Through Manipulation Of Circulating Factors, Edward Koellhoffer

Dissertations & Theses (Open Access)

The aging population of the United States is expanding at an alarming rate. The Center for Disease Control and Prevention estimates that the population of those age 65 years and older will reach over 50 million by 2020 and will double to 100 million by 2060. This will not only put a massive strain on national healthcare resources, but will also increase the number of those who are not able to live and function independently. It is becoming increasingly vital to understand how the brain changes with age and mechanisms to possibly protect and rejuvenate the aged brain to a …

Mechanisms Of Microglia Mediated Apolipoprotien E Neurotoxicity, Pardeep Singh

Dissertations and Theses

No abstract provided.

Induction Of Cerebral Hyperexcitability By Peripheral Viral Challenge: Role Of Cxcl10 Chemokine, Tiffany J. Petrisko

Graduate Theses, Dissertations, and Problem Reports

Peripheral viral infections are po­tent comorbid factors that exacerbate neuro­degene­ration. Although the under­lying mecha­nisms have not been defined, neuronal hyperexcitability has been established as an underlying feature. Our lab has developed a preclinical model in which a viral mimetic, poly­inosinic-poly­cytidylic acid (PIC) is injected in­tra­peritoneally to induce an anti-viral acute phase response (APR). APR in turn elicits robust neuronal hyperexcitability. The present study was undertaken to characterize molecular mechanisms that mediate the development of hyperexcitability in response to PIC challenge. The analysis of brain tissue after PIC challenge revealed a robust elevation of CXCL10 chemokine, indicating its putative role in …

White Matter Inflammation And Executive Dysfunction: Implications For Alzheimer Disease And Vascular Cognitive Impairment, Alexander Levit

Electronic Thesis and Dissertation Repository

White matter integrity is crucial to healthy executive function, the cognitive domain that enables functional independence. However, in the ageing brain, white matter is highly vulnerable. White matter inflammation increases with age and Alzheimer disease (AD), which disrupts the normal function of white matter. This may contribute to executive dysfunction, but the relationship between white matter inflammation and executive function has not been directly evaluated in ageing nor AD. White matter is also particularly vulnerable to cerebrovascular disease, corresponding with the common presentation of executive dysfunction in vascular cognitive impairment (VCI). Thus, white matter may be an important substrate by …

Mechanisms Regulating Axon Initial Segment Stability, Savannah D. Benusa

Theses and Dissertations

Axon initial segment (AIS) disruption has been described in a number of pathological environments where neuroinflammation is a contributing factor; however, whether this disruption is reversible in unknown. To address the principle of AIS structural recovery, we employed an acute neuroinflammatory model. Acute neuroinflammation induced disruption of AIS structural and functional domains and, importantly, upon resolution of neuroinflammatory conditions, was reversed.

Consistent with other studies, we observed a close interaction of microglia with AISs, and utilized this acute neuroinflammatory model to investigate the relationship between reactive microglia and AIS integrity. Gene expression analysis of microglial transcription profiles identified reactive oxygen …

Characterization Of Pro-Inflammatory And Anti-Inflammatory Microglia In The Anterior Cingulate Cortex In Autism Spectrum Disorder, Aubrey N. Sciara

Electronic Theses and Dissertations

Autism spectrum disorder (ASD) is associated with functional abnormalities of the anterior cingulate cortex (ACC), a brain area that mediates social behavior. Given evidence of a role of inflammation in ASD, markers of pro-inflammatory and anti-inflammatory microglia were studied using postmortem ACC tissues from ASD and age-matched typically developed control donors. Gene expression levels of pro-inflammatory (CD68, HLA-DRA, IL1B, NOS2, PTGS2) and anti-inflammatory (ARG1, IGF1, MRC1, PPARG) microglial genes were measured using quantitative real-time PCR. Additionally, brain sections were immunohistochemically stained for a microglial marker. Expression levels of IGF1 were modestly higher, while the expression of …

Mechanisms Of Neural Precursor Cell Apoptosis By Microglia-Derived Cytokines, Jennifer Guadagno

Electronic Thesis and Dissertation Repository

The persistence of neural precursor cells (NPCs) in distinct niches of the adult brain and spinal cord provides an important opportunity for regeneration in the affected nervous system. In the adult brain, neural precursor cells (NPCs) generate new neurons that can be integrated into the CNS circuitry to replace damaged or lost neurons, and contribute to learning and memory processes. Deregulated neurogenesis has been observed under both acute and chronic neurological conditions including stroke, Alzheimer’s disease, and Parkinson’s disease. The extent to which neurogenesis contributes to brain repair is severely limited by the neuroinflammatory processes associated with these neurodegenerative conditions. …