Neurosciences Commons^™

Rotenone Induces Regionally Distinct Α-Synuclein Protein Aggregation And Activation Of Glia Prior To Loss Of Dopaminergic Neurons In C57bl/6 Mice, Savannah M Rocha, Collin M Bantle, Tawfik Aboellail, Debotri Chatterjee, Richard Jay Smeyne, Ronald B Tjalkens

Department of Neuroscience Faculty Papers

Rotenone is a naturally occurring insecticide that inhibits mitochondrial complex I and leads to neurochemical and neuropathological deficits closely resembling those in Parkinson's disease (PD). Deficits include loss of dopaminergic neurons (DAn) in the substantia nigra pars compacta (SNpc), decreased dopamine levels and aggregation of misfolded alpha-synuclein (p129). In rat models of rotenone-induced parkinsonism, the progression of neuronal injury has been associated with activation of microglia and astrocytes. However, these neuroinflammatory changes have been challenging to study in mice, in part because the systemic rotenone exposure model utilized in rats is more toxic to mice. To establish a reproducible murine …

Prostacyclin Promotes Degenerative Pathology In A Model Of Alzheimer’S Disease, Tasha R. Womack, Craig T. Vollert, Odochi Ohia-Nwoko, Monika Schmitt, Saghi Montazari, Tina L. Beckett, David Mayerich, Michael Paul Murphy, Jason L. Eriksen

Sanders-Brown Center on Aging Faculty Publications

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is the most common form of dementia in aged populations. A substantial amount of data demonstrates that chronic neuroinflammation can accelerate neurodegenerative pathologies. In AD, chronic neuroinflammation results in the upregulation of cyclooxygenase and increased production of prostaglandin H2, a precursor for many vasoactive prostanoids. While it is well-established that many prostaglandins can modulate the progression of neurodegenerative disorders, the role of prostacyclin (PGI2) in the brain is poorly understood. We have conducted studies to assess the effect of elevated prostacyclin biosynthesis in a mouse model of AD. Upregulated prostacyclin expression …

Current And Novel Neuroregenerative Therapies, Arrin Brooks

Theses, Dissertations and Capstones

Underlying the physical and cognitive deficits consequent of many neuropathologies is one common factor, the loss of neurons. While neurodegenerative diseases, stroke, and traumatic brain injury arise from a variety of etiologies, they all ultimately result in injury and/or death of neuronal cells and concomitant functional deficits. In the present work we primarily focus on current and potential treatments for localized lesions, particularly those in the striatum of Parkinson’s disease (PD) or the cortex as in stroke. First, we discuss a new surgical technique for deep brain stimulator (DBS) placement, as DBS is a mainstay treatment for movement disorders including …

The Importance Of Protein Context In Spinocerebellar Ataxia Type 3, Sean Luis Johnson

Wayne State University Dissertations

Spinocerebellar Ataxia Type 3 (SCA3) is a member of the family of polyglutamine (polyQ) neurodegenerative disorders that includes Huntington's Disease and several other SCAs. SCA3, the most common dominant ataxia in the world, is caused by polyQ tract expansion in the protein, ataxin-3. How SCA3 occurs and how to treat it remain unresolved issues. The primary culprit of toxicity in all polyQ diseases is the glutamine repeat: its abnormal expansion leads to neuronal dysfunction and death. With that said, there is indisputable evidence that the way polyQ-dependent toxicity presents—areas impacted, cellular processes perturbed—is predicated in large part on regions outside …

Mammalian Target Of Rapamycin Cell Signaling Pathway In Phosphatase And Tensin Homolog Induced Kinase 1 Knockout Rat Model Of Familial Parkinson's Disease, Martha Helena Mortell

Theses and Dissertations--Medical Sciences

More than 10 million people are living with Parkinson’s disease (PD), one million of which are people in the United States. PD is the second most common age-related neurodegenerative disorder, after Alzheimer’s disease, and is characterized by the accumulation of a-synuclein aggregates and the degeneration of dopaminergic neurons. The loss of endogenous dopamine in PD brain accounts for the motor decline presented clinically in PD patients. Etiological factors of PD include oxidative damage and inflammation, although the detailed mechanisms remain unknown. Risk factors for PD include gender, age, environmental factors, and gene mutations.

The current thesis research employed phosphatase and …

Pathogenic Tau Accelerates Aging-Associated Activation Of Transposable Elements In The Mouse Central Nervous System, Paulino Ramirez, Gabrielle Zuniga, Wenyan Sun, Adrian Beckmann, Elizabeth Ochoa, Sarah L Devos, Bradley Hyman, Gabriel Chiu, Ethan R Roy, Wei Cao, Miranda Orr, Virginie Buggia-Prevot, William J Ray, Bess Frost

Faculty, Staff and Student Publications

Transposable elements comprise almost half of the mammalian genome. A growing body of evidence suggests that transposable element dysregulation accompanies brain aging and neurodegenerative disorders, and that transposable element activation is neurotoxic. Recent studies have identified links between pathogenic forms of tau, a protein that accumulates in Alzheimer's disease and related "tauopathies," and transposable element-induced neurotoxicity. Starting with transcriptomic analyses, we find that age- and tau-induced transposable element activation occurs in the mouse brain. Among transposable elements that are activated at the RNA level in the context of brain aging and tauopathy, we find that the endogenous retrovirus (ERV) class …

Myeloid Arginase 1 Insufficiency Exacerbates Amyloid-Β Associated Neurodegenerative Pathways And Glial Signatures In A Mouse Model Of Alzheimer’S Disease: A Targeted Transcriptome Analysis, Chao Ma, Jerry B. Hunt, Andrii Kovalenko, Huimin Liang, Maj-Linda B. Selenica, Michael B. Orr, Bei Zhang, John C. Gensel, David J. Feola, Marcia N. Gordon, Dave Morgan, Paula C. Bickford, Daniel C. Lee

Sanders-Brown Center on Aging Faculty Publications

Brain myeloid cells, include infiltrating macrophages and resident microglia, play an essential role in responding to and inducing neurodegenerative diseases, such as Alzheimer’s disease (AD). Genome-wide association studies (GWAS) implicate many AD casual and risk genes enriched in brain myeloid cells. Coordinated arginine metabolism through arginase 1 (Arg1) is critical for brain myeloid cells to perform biological functions, whereas dysregulated arginine metabolism disrupts them. Altered arginine metabolism is proposed as a new biomarker pathway for AD. We previously reported Arg1 deficiency in myeloid biased cells using lysozyme M (LysM) promoter-driven deletion worsened amyloidosis-related neuropathology and behavioral impairment. However, …

Development Of A Novel Cognitive-Motor Dual Task Assessment Battery In Neurodegenerative Disease, Jason Longhurst

UNLV Theses, Dissertations, Professional Papers, and Capstones

Automaticity --- the ability to perform a task with directing attentional resources to its completion --- is commonly reduced among individuals with neurodegenerative diseases. These automaticity deficits result in impaired functional and daily activities and are sensitive to subtle, subclinical impairments. However, current measurement of automaticity by dual task paradigms is methodologically limited. In order to gain insight into the current state of the literature regarding cognitive-motor interference in symptomatic and prodromal neurodegenerative disease, the author of this dissertation conducted a scoping review (Chapter 1). To address the methodological limitations of current measurement of automaticity, a new measurement tool was …

Dystrophic Microglia Are Associated With Neurodegenerative Disease And Not Healthy Aging In The Human Brain, Ryan K. Shahidehpour, Rebecca E. Higdon, Nicole G. Crawford, Janna H. Neltner, Eseosa T. Ighodaro, Ela Patel, Douglas Price, Peter T. Nelson, Adam D. Bachstetter

Spinal Cord and Brain Injury Research Center Faculty Publications

Loss of physiological microglial function may increase the propagation of neurodegenerative diseases. Cellular senescence is a hallmark of aging; thus, we hypothesized age could be a cause of dystrophic microglia. Stereological counts were performed for total microglia, 2 microglia morphologies (hypertrophic and dystrophic) across the human lifespan. An age-associated increase in the number of dystrophic microglia was found in the hippocampus and frontal cortex. However, the increase in dystrophic microglia was proportional to the age-related increase in the total number of microglia. Thus, aging alone does not explain the presence of dystrophic microglia. We next tested if dystrophic microglia could …

Mitochondrial Aspects Of Neuronal Pathology In Triple-Transgenic Alzheimer’S Disease Mice, John Zachary Cavendish

Graduate Theses, Dissertations, and Problem Reports (ETD)

Alzheimer’s disease (AD) is a fatal, progressive neurodegenerative disease afflicting millions of people in the United States alone and is the only one of the top leading causes of morbidity and mortality with no effective disease-modifying therapies. It is the most common form of dementia, affecting one in three people over the age of 85. While the hallmarks of the disease include accumulation of beta-amyloid-based extracellular plaques and hyperphosphorylated tau-based intracellular neurofibrillary tangles, treatment strategies centered on removing or mitigating these components of AD have all failed in humans. Mitochondrial dysfunction has been increasingly recognized as an early and consistent …

Tdp-43 Mediated Blood-Brain Barrier Permeability And Leukocyte Infiltration Promote Neurodegeneration In A Low-Grade Systemic Inflammation Mouse Model, Frank Zamudio, Anjanet R. Loon, Shayna Smeltzer, Khawla Benyamine, Nanda K. Navalpur Shanmugam, Nicholas J. F. Stewart, Daniel C. Lee, Kevin Nash, Maj-Linda B. Selenica

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Neuronal cytoplasmic inclusions containing TAR DNA-binding protein 43 (TDP-43) are a neuropathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's Disease (AD). Emerging evidence also indicates that systemic inflammation may be a contributor to the pathology progression of these neurodegenerative diseases.

METHODS: To investigate the role of systemic inflammation in the progression of neuronal TDP-43 pathology, AAV9 particles driven by the UCHL1 promoter were delivered to the frontal cortex of wild-type aged mice via intracranial injections to overexpress TDP-43 or green fluorescent protein (GFP) in corticospinal motor neurons. Animals were then subjected …

Expanding The Search For Genetic Biomarkers Of Parkinson's Disease Into The Living Brain, Simon M. Benoit, Hu Xu, Susanne Schmid, Roumiana Alexandrova, Gaganjot Kaur, Bhooma Thiruvahindrapuram, Sergio L. Pereira, Mandar Jog, Matthew O. Hebb

Brain and Mind Institute Researchers' Publications

Altered gene expression related to Parkinson's Disease (PD) has not been described in the living brain, yet this information may support novel discovery pertinent to disease pathophysiology and treatment. This study compared the transcriptome in brain biopsies obtained from living PD and Control patients. To evaluate the novelty of this data, a comprehensive literature review also compared differentially expressed gene (DEGs) identified in the current study with those reported in PD cadaveric brain and peripheral tissues. RNA was extracted from rapidly cryopreserved frontal lobe specimens collected from PD and Control patients undergoing neurosurgical procedures. RNA sequencing (RNA-Seq) was performed and …

Alzheimer's And Amyloid Beta: Amyloidogenicity And Tauopathy Via Dyshomeostatic Interactions Of Amyloid Beta, Jordan Tillinghast

Senior Honors Theses

This paper reviews functions of Amyloid-β (Aβ) in healthy individuals compared to the consequences of aberrant Aβ in Alzheimer’s disease (AD). As extraneuronal Aβ accumulation and plaque formation are characteristics of AD, it is reasonable to infer a pivotal role for Aβ in AD pathogenesis. Establishing progress of the disease as well as the mechanism of neurodegeneration from AD have proven difficult (Selkoe, 1994). This thesis provides evidence suggesting the pathogenesis of AD is due to dysfunctional neuronal processes involving Aβ’s synaptic malfunction, abnormal interaction with tau, and disruption of neuronal homeostasis. Significant evidence demonstrates that AD symptoms are partially …

Micrornas And The Genetic Nexus Of Brain Aging, Neuroinflammation, Neurodegeneration, And Brain Trauma, Saumyendra N. Sarkar, Ashley E. Russell, Russell Elizabeth B. Engler-Chiurazzi, Keyana N. Porter, James W. Simpkins

Faculty & Staff Scholarship

ABSTRACT: Aging is a complex and integrated gradual deterioration of cellular activities in specific organs of the body, which is associated with increased mortality. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, neurovascular disorders, and neurodegenerative diseases. There are nine tentative hallmarks of aging. In addition, several of these hallmarks are increasingly being associated with acute brain injury conditions. In this review, we consider the genes and their functional pathways involved in brain aging as a means of developing new strategies for therapies targeted to the neuropathological processes themselves, but also as …

A Synthetic Agonist To Vasoactive Intestinal Peptide Receptor-2 Induces Regulatory T Cell Neuroprotective Activities In Models Of Parkinson's Disease, R. Lee Mosley, Yaman Lu, Katherine E. Olson, Jatin Machhi, Wenhui Yan, Krista L. Namminga, Jenell R. Smith, Scott J. Shandler, Howard Gendelman

Journal Articles: Pharmacology & Experimental Neuroscience

A paradigm shift has emerged in Parkinson's disease (PD) highlighting the prominent role of CD4⁺ Tregs in pathogenesis and treatment. Bench to bedside research, conducted by others and our own laboratories, advanced a neuroprotective role for Tregs making pharmacologic transformation of immediate need. Herein, a vasoactive intestinal peptide receptor-2 (VIPR2) peptide agonist, LBT-3627, was developed as a neuroprotectant for PD-associated dopaminergic neurodegeneration. Employing both 6-hydroxydopamine (6-OHDA) and α-synuclein (α-Syn) overexpression models in rats, the sequential administration of LBT-3627 increased Treg activity without altering cell numbers both in naïve animals and during progressive nigrostriatal degeneration. LBT-3627 administration was linked to …

Autologous Peripheral Nerve Grafts To The Brain For The Treatment Of Parkinson's Disease, Andrew Welleford

Theses and Dissertations--Neuroscience

Parkinson’s disease (PD) is a disorder of the nervous system that causes problems with movement (motor symptoms) as well as other problems such as mood disorders, cognitive changes, sleep disorders, constipation, pain, and other non-motor symptoms. The severity of PD symptoms worsens over time as the disease progresses, and while there are treatments for the motor and some non-motor symptoms there is no known cure for PD. Thus there is a high demand for therapies to slow the progressive neurodegeneration observed in PD. Two clinical trials at the University of Kentucky College of Medicine (NCT02369003, NCT01833364) are currently underway that …

Cyclophilin 40 As A Novel Disaggregase, Jeremy Dustin Baker

USF Tampa Graduate Theses and Dissertations

The negative health and economic impacts of neurodegenerative diseases on Americans is astounding and accelerating with an aging population. The Alzheimer’s Association reports that 5.7 million Americans suffer from Alzheimer’s disease (AD), a number which is expected to increase to 14 million by 2050. In economic terms, AD and other neurodegenerative disorders will cost the US over $275 billion in 2018, rising to over $1 trillion annually by 2050. AD causes gross brain atrophy and is most damaging throughout the cortex and the hippocampus, regions required for higher cognitive function and memory. AD presents as tangles within neurons composed of …

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 …

Gender- And Region-Specific Changes In Estrogen Signaling In Aging Rat Brain Mitochondria, Christopher M. Evola, Tanner L. Hudson, Luping Huang, Adrian M. Corbett, Debra A. Mayes

Neuroscience, Cell Biology & Physiology Faculty Publications

Recently epidemiological studies suggest females lose neuroprotection from neurodegenerative diseases as they go through menopause. It has been hypothesized that this neuroprotection is hormone‐dependent. The current study characterized cell signaling molecules downstream of estrogen receptor beta that are known to play a role in memory, PKC, ERK, and connexin‐43, in regions of the brain associated with memory decline in an attempt to elucidate significant changes that occur post‐estrus. Total whole cell lysates were compared to isolated mitochondrial protein because mitochondrial function is known to be altered during aging. As hypothesized, protein concentrations differed depending on age, gender, and brain region. …

Apoe And Alzheimer’S Disease: Neuroimaging Of Metabolic And Cerebrovascular Dysfunction, Jason A. Brandon, Brandon C. Farmer, Holden C. Williams, Lance A. Johnson

Physiology Faculty Publications

Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for late onset Alzheimer’s Disease (AD), and is associated with impairments in cerebral metabolism and cerebrovascular function. A substantial body of literature now points to E4 as a driver of multiple impairments seen in AD, including blunted brain insulin signaling, mismanagement of brain cholesterol and fatty acids, reductions in blood brain barrier (BBB) integrity, and decreased cerebral glucose uptake. Various neuroimaging techniques, in particular positron emission topography (PET) and magnetic resonance imaging (MRI), have been instrumental in characterizing these metabolic and vascular deficits associated with this important AD risk factor. In …

Regional Microglia Are Transcriptionally Distinct But Similarly Exacerbate Neurodegeneration In A Culture Model Of Parkinson's Disease., Eric Wildon Kostuk, Jingli Cai, Lorraine Iacovitti

Department of Neuroscience Faculty Papers

BACKGROUND: Parkinson's disease (PD) is characterized by selective degeneration of dopaminergic (DA) neurons of the substantia nigra pars compacta (SN) while neighboring ventral tegmental area (VTA) DA neurons are relatively spared. Mechanisms underlying the selective protection of the VTA and susceptibility of the SN are still mostly unknown. Here, we demonstrate the importance of balance between astrocytes and microglia in the susceptibility of SN DA neurons to the PD mimetic toxin 1-methyl-4-phenylpyridinium (MPP

METHODS: Previously established methods were used to isolate astrocytes and microglia from the cortex (CTX), SN, and VTA, as well as embryonic midbrain DA neurons from the …

Astaxanthin Attenuates Mptp Induced Neurotoxicity And Modulates Cognitive Function In Aged Mice, Beth Grimmig

USF Tampa Graduate Theses and Dissertations

Parkinson’s disease is the second common neurodegenerative disease and is most frequently diagnosed in individuals over 60. There are no available medications that can prevent or restore the loss of neurons that correspond to motor impairments in patients. Identifying novel therapeutic compounds that are capable of slowing and reversing the extensive neurodegeneration that occurs in PD remains an important goal of the field. While basic research has identified potential therapeutic agents, studies often use young model organisms to demonstrate efficacy of the target compound. This approach ignores the impact of the aged CNS on the disease process, and likely contributes …

Induction Of Mir-155 After Brain Injury Promotes Type 1 Interferon And Has A Neuroprotective Effect., Emily Harrison, Kathleen M. Emanuel, Benjamin G. Lamberty, Brenda M. Morsey, Min Li, Matthew L. Kelso, Sowmya V. Yelamanchili, Howard S. Fox

Journal Articles: Pharmacology & Experimental Neuroscience

Traumatic brain injury (TBI) produces profound and lasting neuroinflammation that has both beneficial and detrimental effects. Recent evidence has implicated microRNAs (miRNAs) in the regulation of inflammation both in the periphery and the CNS. We examined the expression of inflammation associated miRNAs in the context of TBI using a mouse controlled cortical impact (CCI) model and found increased levels of miR-21, miR-223 and miR-155 in the hippocampus after CCI. The expression of miR-155 was elevated 9-fold after CCI, an increase confirmed by in situ hybridization (ISH). Interestingly, expression of miR-155 was largely found in neuronal nuclei as evidenced by co-localization …

Analysis Of The Secondary Neurodegenerative Consequences Of Primary Oligodendrocyte Stress Through The Use Of The Novel Obiden Mouse Model, Daniel Zdzislaw Radecki

Wayne State University Dissertations

The work of this project was to develop, test and characterize a potential novel mouse model of the neurodegenerative disease Multiple Sclerosis (MS). Historically, MS has been identified as a primary autoimmune disease of the central nervous system (CNS). However, treatments based on this view have met with limited success, and in most cases, fail to prevent progression of MS from mild to moderate and severe forms. Original observations regarding axonal and neuronal pathology in the white and gray matter of the CNS were rediscovered in the 1990s. These observations indicated that even in the absence of the immune system, …

Prior Binge Ethanol Exposure Potentiates The Microglial Response In A Model Of Alcohol-Induced Neurodegeneration, Simon Alex Marshall, Chelsea Rhea Geil Nickell, Kimberly Nixon

Pharmaceutical Sciences Faculty Publications

Excessive alcohol consumption results in neurodegeneration which some hypothesize is caused by neuroinflammation. One characteristic of neuroinflammation is microglial activation, but it is now well accepted that microglial activation may be pro- or anti-inflammatory. Recent work indicates that the Majchrowicz model of alcohol-induced neurodegeneration results in anti-inflammatory microglia, while intermittent exposure models with lower doses and blood alcohol levels produce microglia with a pro-inflammatory phenotype. To determine the effect of a repeated binge alcohol exposure, rats received two cycles of the four-day Majchrowicz model. One hemisphere was then used to assess microglia via immunohistochemistry and while the other was used …

Antibodies To Heterogenous Nuclear Ribonucleoprotein A1 Penetrate Neurons Leading To Multiple Downstream Effects Resulting In Neurodegeneration, Joshua Nathan Douglas

Theses and Dissertations (ETD)

Multiple sclerosis (MS) is the most common demyelinating disorder of the central nervous system. MS is believed to occur in genetically susceptible individuals due to an unknown environmental stimulus. MS patients produce autoantibodies to heterogenous nuclear ribonuclearprotein A1 (hnRNP A1), an RNA binding protein (RBP) highly expressed in neurons. hnRNP A1 functions in pre-mRNA splicing, mRNA trafficking, and translation. Furthermore, the anti-hnRNP A1 antibodies are specific to a N-terminal region termed ‘M9’ which serves as a nuclear export sequence/nuclear localization sequence (NES/NLS) responsible for nuclear/cytoplasmic transport of the protein. In this manuscript we will provide data revealing that anti-hnRNP A1 …

Histological And Behavioral Consequences Of Repeated Mild Traumatic Brain Injury In Mice, Amanda Nicholle Bolton Hall

Theses and Dissertations--Physiology

The majority of the estimated three million traumatic brain injuries that occur each year are classified as “mild” and do not require surgical intervention. However, debilitating symptoms such as difficulties focusing on tasks, anxiety, depression, and visual deficits can persist chronically after a mild traumatic brain injury (TBI) even if an individual appears “fine”. These symptoms have been observed to worsen or be prolonged when an individual has suffered multiple mild TBIs. To test the hypothesis that increasing the amount of time between head injuries can reduce the histopathological and behavioral consequences of repeated mild TBI, a mouse model of …

Dual Destructive And Protective Roles Of Adaptive Immunity In Neurodegenerative Disorders., Kristi M. Anderson, Katherine E. Olson, Katherine A. Estes, Ken Flanagan, Howard E. Gendelman, R. Lee Mosley

Journal Articles: Pharmacology & Experimental Neuroscience

Inappropriate T cell responses in the central nervous system (CNS) affect the pathogenesis of a broad range of neuroinflammatory and neurodegenerative disorders that include, but are not limited to, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson's disease. On the one hand immune responses can exacerbate neurotoxic responses; while on the other hand, they can lead to neuroprotective outcomes. The temporal and spatial mechanisms by which these immune responses occur and are regulated in the setting of active disease have gained significant recent attention. Spatially, immune responses that affect neurodegeneration may occur within or outside the CNS. Migration of …

Investigating Therapeutic Options For Lafora Disease Using Structural Biology And Translational Methods, Amanda R. Sherwood

Theses and Dissertations--Molecular and Cellular Biochemistry

Lafora disease (LD) is a rare yet invariably fatal form of epilepsy characterized by progressive degeneration of the central nervous and motor systems and accumulation of insoluble glucans within cells. LD results from mutation of either the phosphatase laforin, an enzyme that dephosphorylates cellular glycogen, or the E3 ubiquitin ligase malin, the binding partner of laforin. Currently, there are no therapeutic options for LD, or reported methods by which the specific activity of glucan phosphatases such as laforin can be easily measured. To facilitate our translational studies, we developed an assay with which the glucan phosphatase activity of laforin as …

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 …