Nervous System Diseases Commons^™

Cocaine Upregulates Microglial Lipid Droplet Formation Through Increasing Lipid Synthesis Activity In Vitro And In Vivo, Yan Cheng, Brooke Russell, Liam Liyang Guo, Aryan Patel, Yan Y. Sanders, Ming-Lei Guo

Department of Biomedical and Translational Sciences Faculty Publications

A novel subtype of microglia, lipid droplet accumulation microglia (LDAMs), has been identified in the aged brain, which is characterized by sustained inflammation and senescent-like phenotypes. LDAMs are deeply involved in promoting brain aging as well as the pathogenesis of multiple neurodegenerative diseases. Cocaine can alter brain lipidomic profiles, induce microglial activation, and accelerate brain aging. This suggests that cocaine might affect microglial lipid metabolism, which ultimately aggravates aging-related neurological disorders in people with addictions. In this study, we explored the effects of cocaine on microglial lipid metabolism. Our results showed that chronic cocaine administration altered brain lipid profiles and …

Microbial Metabolite Regulation Of Microglial Ahr Signaling In Alzheimer’S Disease, Ghalya E. Alrousan

Dissertations and Theses (Open Access)

Introduction: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β plaque accumulation, neuroinflammation, and cognitive decline. Recent evidence suggests that systemic factors, particularly the gut microbiota and its metabolites, play a significant role in shaping brain immune responses, including microglial activation. However, the mechanisms linking gut dysbiosis to microglial dysfunction in AD are poorly understood. The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor responsive to tryptophan metabolites, has recently gained attention as a key regulator of neuroinflammation and microglial function. I hypothesize that the loss of beneficial microbial AHR ligands, specifically indole derivatives, during aging and AD …

Radial Glia Integrin Avb8 Regulates Cell Autonomous Microglial Tgfβ1 Signaling That Is Necessary For Microglial Identity, Gabriel Mckinsey, Nicolas Santander, Xiaoming Zhang, Kilian Kleemann, Lauren Tran, Aditya Katewa, Kaylynn Conant, Matthew Barraza, Kian Waddell, Carlos Lizama, Marie La Russa, Ji Hyun Koo, Hyunji Lee, Dibyanti Mukherjee, Helena Paidassi, E. S. Anton, Kamran Atabai, Dean Sheppard, Oleg Butovsky, Thomas Arnold

Department of Medicine Faculty Papers

Microglial diversity arises from the interplay between inherent genetic programs and external environmental signals. However, the mechanisms by which these processes develop and interact within the growing brain are not yet fully understood. Here, we show that radial glia-expressed integrin beta 8 (ITGB8) activates microglia-expressed TGFβ1 to drive microglial development. Domain-restricted deletion of Itgb8 in these progenitors results in regionally restricted and developmentally arrested microglia that persist into adulthood. In the absence of autocrine TGFβ1 signaling, microglia adopt a similar phenotype, leading to neuromotor symptoms almost identical to Itgb8 mutant mice. In contrast, microglia lacking the canonical TGFβ signal transducers …

Cell-Type Specific Apoe4 To Apoe2 ‘Switching’ In Astrocytes And Microglia Alters Alzheimer’S Disease Neuropathology, Lesley R. Golden

Theses and Dissertations--Physiology

Apolipoprotein E (APOE) is the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD). APOE exists in three common protein isoforms throughout the population: ApoE2 (E2), ApoE3 (E3), and ApoE4 (E4). While APOE allele frequencies and the degree of AD-associated risk vary across different ethnic groups, when compared to the ‘neutral’ and most common E3 allele, the E4 allele confers up to a 33-fold increase in Alzheimer’s Disease (AD) risk. Conversely, the neuroprotective E2 allele decreases AD risk by up to 67%. Here, we aimed to determine the therapeutic potential of cell-type specific APOE allele ‘switching’ and explore …

In Vivo Examination Of Peripheral Drivers Of Alzheimer’S Disease, Celso Catumbela

Dissertations and Theses (Open Access)

Alzheimer’s disease (AD) is the leading cause of dementia worldwide, and predominantly affects elderly populations. This disease is well known for its effects on the brain, but a wealth of clinical reports show that dementia can also modify, or be modified by, various peripheral and systemic processes. Yet, the pathological contribution of peripheral comorbidities to AD remains to be fully understood. In an attempt to address some knowledge gaps, we characterized the cerebral and peripheral pathology in mice with history of either liver injury or sepsis. In the former subjects, we found that even in the absence of genetic risk …

Deciphering The Contribution Of Microglia To Neurodegeneration In Friedreich's Ataxia, Sydney N. Gillette

Master's Theses

Friedreich's ataxia (FRDA) is the most prevalent inherited ataxia, affecting one in every 50,000 individuals in the United States. This hereditary condition is caused by an abnormal GAA trinucleotide repeat expansion within the first intron of the frataxin gene resulting in decreased levels of the frataxin protein (FXN). Insufficient cellular frataxin levels results in iron accumulation, increased reactive oxygen species production and mitochondrial dysfunction. Tissues most heavily impacted are those most dependent on oxidative phosphorylation as an energy source and include the nervous system and muscle tissue. This is evident in the clinical phenotype which includes muscle weakness, ataxia, neurodegeneration …

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 …

Retinoid X Receptor As A Mediator Of Post Stroke Recovery By Reversing Age-Associated Phenotypes Of Microglia/Macrophages, Shun-Ming Ting

Dissertations and Theses (Open Access)

After stroke, microglia (MG) and blood-derived macrophages, together (MF), clear dead cells and cellular debris in the infarcted brain through phagocytosis. However, the phagocytic capability of MF declines with age. Age-related changes in MF phenotype also include overactive inflammatory responses to stroke-induced brain injury, altogether resulting in poor recovery after stroke. Retinoid-X-receptor (RXR) is a pleiotropic transcription factor. Our studies suggest that RXRa enhances MF phagocytic functions, reduces inflammatory responses, and improves post-stroke recovery. To establish phenotypes of aging MF, MG were MACS-sorted from the brains of young adults (2-4 months old) and aged (18-20 months old) mice for transcriptomic …

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 …

The Effects Of A Blood–Brain Barrier Penetrating Erythropoietin In A Mouse Model Of Tauopathy, Joshua Yang, Weijun Ou, Nataraj Jagadeesan, Juste Simanauskaite, Jiahong Sun, Demi M. Castellanos, David H. Cribbs, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Erythropoietin (EPO), a hematopoietic neurotrophin, is a potential therapeutic for Alzheimer’s disease (AD) but has limited blood–brain barrier (BBB) permeability. EPO fused to a chimeric transferrin receptor monoclonal antibody (cTfRMAb) enters the brain via TfR-mediated transcytosis across the BBB. We previously showed that cTfRMAb-EPO is protective in a mouse model of amyloidosis, but its effects on tauopathy are not known. Given that amyloid and tau pathology are characteristics of AD, the effects of cTfRMAb-EPO were studied in a tauopathy mouse model (PS19). Six-month-old PS19 mice were injected intraperitoneally with either saline (PS19-Saline; n = 9) or cTfRMAb-EPO (PS19-cTfRMAb-EPO, 10 mg/kg; …

Glial Cell-Specific Contribution Of Pkr-Like Er Kinase (Perk) In Neuroinflammation And Behavior, Anirudhya Lahiri

Graduate Theses, Dissertations, and Problem Reports (ETD)

Neurological disorders such as multiple sclerosis (MS) are a major public health concern in the US, with no available therapeutic cure. Chronic neuroinflammation and aberrant proteostasis in the central nervous system (CNS) are the major hallmarks of neurological diseases. Endoplasmic Reticulum (ER) is a major cellular organelle involved in protein synthesis, folding and maturation of various secretory and transmembrane proteins. Pathophysiological stressors such as trauma and infection result in misfolded protein accumulation in the endoplasmic reticulum (ER) lumen, which results in ER stress. To regain proteostasis (protein homeostasis), cells activate the unfolded protein response (UPR). UPR is an evolutionarily conserved …

Exploring The Viability Of A Microglia Attenuating Treatment Model For Fibromyalgia Patients, Rohan Yarlagadda

Rowan-Virtua Research Day

Fibromyalgia refers to a rheumatic condition experienced as pain all over the body without a specific cause. This is considered a diagnosis of exclusion. This classification seems to suggest that any treatment options for it are purely symptomatic and are not disease targeted. Its complex diagnosis and underlying pathology contribute to the challenge of medically addressing fibromyalgia. Without a strict cause, fibromyalgia is often treated symptomatically with CBT and SNRIs. However, recent research suggests that existing therapeutic approaches are not very effective, especially when considering long term benefits for this chronic condition. This beckons for novel treatment options for these …

Ameliorative Effects Of Minor Cannabinoids Over Hiv-1 Tat-Mediated Visceral Pain, Charlie Worth

Honors Theses

As the total number of people living with HIV continues to rise across the world, an effective HIV treatment is still sought after. While modern-day advanced therapies exist for mitigating much of the negative effects of HIV, the virus remains evasive and problematic in the central nervous system. Thus, even with treatment, many people living with HIV continue to suffer from a plethora of symptoms. However, a large proportion of HIV-positive patients claim to feel a reduction in those persevering symptoms after cannabis usage. This anecdotal evidence has sparked interest in the efficacy of cannabis constituents for HIV therapy. This …

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 …

The Role Of Anti-Inflammatory Cytokine Interleukin-10 (Il-10) In Tauopathies, Lea L. Weston

Biomedical Sciences ETDs

Tauopathies are neurodegenerative diseases, including Alzheimer’s disease, that are associated with pathological accumulation of the microtubule associated protein tau (MAPT, or tau) (Lee et al., 2001). Abnormal hyperphosphorylated tau (pTau) strongly correlate with cognitive impairment (Nelson et al., 2012). Neuroinflammation is also associated with tauopathies (Gerhard et al., 2006b; Edison et al., 2008) and is implicated in driving tau pathology (Yoshiyama et al., 2007, Maphis et al., 2015b). Therefore, it is compelling to understand the role of anti-inflammatory cytokines in limiting neuroinflammation and tau pathology. Interleukin-10 (IL-10) is a well-established anti-inflammatory cytokine with roles in limiting inflammation in the central …

Role Of Microglial Amylin Receptors In Mediating Beta Amyloid (Aβ)-Induced Inflammation, Wen Fu, Vlatka Vukojevic, Aarti Patel, Rania Soudy, David Mactavish, David Westaway, Kamaljit Kaur, Valeri Goncharuk, Jack Jhamandas

Pharmacy Faculty Articles and Research

Background: Neuroinflammation in the brain consequent to activation of microglia is viewed as an important component of Alzheimer’s disease (AD) pathology. Amyloid beta (Aβ) protein is known to activate microglia and unleash an inflammatory cascade that eventually results in neuronal dysfunction and death. In this study, we sought to identify the presence of amylin receptors on human fetal and murine microglia and determine whether Aβ activation of the inflammasome complex and subsequent release of cytokines is mediated through these receptors.

Methods: The presence of dimeric components of the amylin receptor (calcitonin receptor and receptor activity modifying protein 3) …

Altered Axon Initial Segment Structure And Function In Inflammatory Disease, Kareem C. Clark

Theses and Dissertations

Axonal pathology is a key contributor to long-term disability in multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), but the mechanisms that underlie axonal insults remain unclear. While most axonal pathologies characterized in MS are a direct consequence of myelin loss, we propose that axonal pathologies also occur independent of demyelination. In support of this idea, we recently reported that mice that develop experimental autoimmune encephalomyelitis (EAE), a model commonly used to mimic the pathogenesis of MS, exhibit a structural and functional disruption of the axon initial segment (AIS), a subdomain of the axon that …

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 …

Pathological Effects Of Repeated Concussive Tbi In Mouse Models: Periventricular Damage And Ventriculomegaly, Richard H. Wolferz Jr.

Honors Scholar Theses

Repeated concussive traumatic brain injury (rcTBI) is the most prominent form of head injury affecting the brain, with an estimated 1.7 million Americans affected each year (Kuhn 2012). Neurologists have been concerned about the danger of repeated head impacts since the 1920’s, but researchers have only begun to understand the long-term effects of rcTBI (McKee 2009). Although symptoms can be as mild as dizziness, current research suggests that multiple concussions can lead to a progressive degenerative brain disease known as chronic traumatic encephalopathy (CTE) (Luo 2008, McKee 2009, Kane 2013). Research on the brain is just beginning to scratch the …

Modified Amino Acid Copolymers Suppress Myelin Basic Protein 85–99-Induced Encephalomyelitis In Humanized Mice Through Different Effects On T Cells, Zsolt Illés, Joel N.H. Stern, Jay Reddy, Hanspeter Waldner, Marcin P. Mycko, Celia F. Brosnan, Stephan Ellmerich, Daniel M. Altmann, Laura Santambrogio, Jack L. Strominger, Vijay K. Kuchroo

Jay Reddy Publications

A humanized mouse bearing the HLA-DR2 (DRA/DRB1*1501) pro- tein associated with multiple sclerosis (MS) and the myelin basic protein (MBP) 85–99-specific HLA-DR2-restricted T cell receptor from an MS patient has been used to examine the effectiveness of modified amino acid copolymers poly(F,Y,A,K)n and poly- (V,W,A,K)n in therapy of MBP 85–99-induced experimental auto-immune encephalomyelitis (EAE) in comparison to Copolymer 1 [Copaxone, poly(Y,E,A,K)n]. The copolymers were designed to optimize binding to HLA-DR2. Vaccination, prevention, and treatment of MBP-induced EAE in the humanized mice with copolymers FYAK and VWAK ameliorated EAE more effectively than Copolymer 1, reduced the number of pathological lesions, and …