Molecular and Cellular Neuroscience Commons^™

Establishment Of A Hek293t Cell Model System To Investigate Direct Intracellular Interactions Between Amyloid-Β (Aβ) And The Nlrp3 Inflammasome, Cristina Sinobas Pereira

Dissertations

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. While Amyloid-β (Aβ) aggregation is a defining pathological feature, increasing evidence highlights chronic neuroinflammation as a critical contributor to disease progression. Soluble Aβ assemblies can act as damage associated molecular patterns (DAMPs) including activation of the NLRP3 inflammasome, which links amyloid pathology to sustained inflammatory responses in the brain (Heneka et al., 2015; Nakanishi et al., 2018). However, the molecular mechanisms by which specific Aβ conformations influence inflammasome assembly remain incompletely understood.This study aimed to investigate whether distinct aggregation states of amyloid β42 (Aβ42) are …

The Role Of Semaphorins In Response To Injury In C. Elegans Neurons, Maria Belen Harreguy Alfonso

Dissertations

When neural tissue is injured by trauma, delicate neuronal processes such as axons and dendrites are prone to lesion damage and often disconnect. The molecular, cellular, and circuit mechanisms that underlie the regrowth and reconnection of these processes and the recovery of behavior are major challenges in the fields of neuroscience, regeneration, and resilience. At the molecular and cellular levels, signaling pathways that mediate neuronal growth cone guidance during development can play a role in neuronal regeneration and recovery from injury. One family of signaling proteins involved in this process comprises the highly conserved semaphorins and their receptors, the plexins. …

Probing Amyloid-Beta Protein Structure And Dynamics With A Selective Antibody, Shikha Grover

Dissertations

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. The AD brain is characterized by significant neuronal loss and accumulation of insoluble fibrillar amyloid-β protein (Aβ) plaques and tau protein neurofibrillary tangles in the brain. However, over the last decade, many studies have shown that the neurodegenerative effect of Aβ may in fact be caused by various soluble oligomeric forms as opposed to the insoluble fibrils. Furthermore, the data suggest that a pre-fibrillar aggregated form, termed protofibrils, mediates direct neurotoxicity, and triggers a robust neuroinflammatory response.

Antibodies targeting the various conformation of Aβ are important therapeutic agents to prevent the progression …

Regulation Of Parkinson’S Disease-Associated Genes By Pumilio Proteins And Micrornas In The Human Neuroblastoma Cell Line Sh-Sy5y, Lisa J. Snoderly-Foster

Dissertations

Parkinson’s disease (PD) is the second most common age-related, neurodegenerative disease. A small collection of genes has been linked to PD, including SNCA encoding the protein alpha-synuclein that aggregates in Lewy bodies, a hallmark of PD. Overexpression of these genes can lead to pathogenesis, yet the regulatory mechanisms that control protein production of the genes are not fully understood. The SH-SY5Y neuronal cell line is a common model for the study of neurodegenerative diseases, including PD. However, SH-SY5Y cells are difficult to transfect, a process necessary for genetic manipulations and downstream analysis of RNA and protein. Herein, I describe the …

Granulins In Norm And Neurodegenerative Pathologies, Anukool Bhopatkar

Dissertations

Granulins (GRNs) are small, cysteine-rich modules produced from the proteolytic cleavage of the precursor protein called progranulin (PGRN). GRNs are present in the form of seven tandem repeats within the precursor and are known to be produced in the extracellular and in lysosomal environments. In physiology, PGRN and GRNs plays pleiotropic roles such as neuronal growth and differentiation, immunomodulation, wound healing. Recent studies have implicated pathological role for PGRN in Alzheimer disease (AD) and frontotemporal dementia (FTD) but specific mechanism(s) remains unclear. However, potential interactions between GRNs and Ab42 and TDP-43 seem like a plausible underlying mechanism. Studies presented here …

Characterizing Galectin And Lysosomal Rupture's Role In Spreading Parkinson Disease Pathology, Kevin Burbidge

Dissertations

The misfolding and subsequent accumulation of alpha-synuclein (α-syn) is central to the pathogenesis of Parkinson's disease (PD). Several lines of evidence suggest pathological α-syn spread cell-to-cell via a "prion-like" mechanism. Furthermore, this pathological α-syn is capable of "seeding" further misfolding of non-pathological α-syn, converting them to the pathological form. While a vast body of both genetic and experimental evidence indicates that α-syn is critical to PD development, how α-syn induces progressive neuronal dysfunction and cell death remains unclear.Autophagy, conventional for macroautophagy, is the primary degradation pathway for α-syn aggregates. Autophagy also influences the unconventional secretion of both pathological and non-pathological …

Cerebro-Vascular Disruption Mediated Initiation And Propagation Of Traumatic Brain Injury In A Fluid Percussion Injury Model, Xiaotang Ma

Dissertations

Traumatic brain injury (TBI) is a major health problem for over 3.17 million people in the US. There is no FDA-approved drug for the treatment because the injury mechanisms have not been clearly identified. The knowledge gap is addressed here by the lateral fluid percussion injury (FPI) rat model, through the understanding of layer-structured mechanisms from physical vascular rupture to acute necrosis, as well as biochemical changes in perivascular space as secondary events.

Firstly, the cerebrovascular hemorrhage and related infarct volume are investigated as the primary events in moderate FPI, which is found to be increased with injury severity in …

Evolution Of Caffeine Biosynthetic Enzymes And Pathways In Flowering Plants, Ruiqi Huang

Dissertations

Convergent evolution generally refers to the independent evolution of similar biological function more than once in unrelated species. Caffeine is thought to have evolved by convergence, and is naturally produced through secondary metabolism in plants to defend against pathogen attack and insect feeding or to attract pollinators. The same caffeine biosynthetic pathway has been elucidated in Camellia (tea) and Coffea (coffee), in which xanthosine is sequentially methylated to caffeine via 7-methylxanthine and theobromine. However, although the same catalysis pathway is used, different (paralogous) enzymes in the SAMT/BAMT/theobromine synthase (SABATH) multigene family are used in the two species. In my dissertation, …

Elucidating Mechanisms Of Protein Aggregation In Alzheimer’S Disease Using Antibody-Based Strategies., Benjamin A. Colvin

Dissertations

Alzheimer’s Disease (AD) is a devastating neurodegenerative disorder. There are two characteristic histopathological hallmarks in the brain: senile plaques and neurofibrillary tangles, composed of insoluble aggregates of the amyloids Amyloid-β (Aβ) and tau protein, respectively. These diagnostic markers, though distinctive, are not apparent effectors of AD pathology. Evidence has mounted suggesting smaller soluble aggregates (oligomers) of Aβ or tau are the true drivers of disease progression. This dissertation presents several amyloid biophysics projects. Aggregate biophysical parameters such as weight, shape, and conformation were measured using a range of methodologies, including Multiangle Light Scattering, Dynamic Light Scattering, UV-Circular Dichroism, UV-Fluorescence, Scanning …

The Molecular Components Of Estrogen Receptor Beta (Erβ) Signaling In Neuronal Sytems, Natasha Mott

Dissertations

With increasing life expectancy, women are now living upwards of 50 years without circulating estrogens, therefore, it is essential to investigate how the brain is changed by estrogen deprivation and also how aging influences these changes. The Women's Health Initiative (WHI) study spurred rigorous debate regarding estrogen therapy for postmenopausal women due to dichotomous effects of estrogens in menopausal and post-menopausal women. Meta-analyses of the WHI study revealed that after circulating estrogens are depleted for many years re-exposure may cause aberrant, negative health effects, indicating that there is an age-related `switch' in estrogen signaling around menopause. These age-related effects of …

Exercise Alters Glial Cell Line-Derived Neurotrophic Factor (Gdnf) Protein Content In The Spinal Cord, Monica Janine Mccullough

Dissertations

Neurotrophic factors may play a role in exercise-induced neuroprotective effects; however, it is not known if exercise mediates changes in glial cell line-derived neurotrophic factor (GDNF) protein levels in the spinal cord. The aim of the studies described herein was to determine if exercise alters GDNF protein expression in the lumbar spinal cord of healthy and diseased animals. The lumbar spinal cord was analyzed from adult rats aged 6-, 12-, 18- and 24-months, and from transgenic amyotrophic lateral sclerosis (ALS) mice and wild-type mice aged 3 months. Animals had undergone either forced wheel running, voluntary wheel running or swimming for …

Integration Of Fetal Neocortical Transplants With The Damaged Host Brain, Mette Katrine Schulz

Dissertations

No abstract provided.