Digital Commons Network^™

Visualization And Quantification Of Post-Stroke Neural Connectivity And Neuroinflammation Using Serial Two-Photon Tomography In The Whole Mouse Brain, Katherine Poinsatte, Dene Betz, Vanessa O. Torres, Apoorva D. Ajay, Shazia Mirza, Uma M. Selvaraj, Erik J. Plautz, Xiangmei Kong, Sankalp Gokhale, Julian P. Meeks, Denise M. O. Ramirez, Mark P. Goldberg, Ann M. Stowe

Neurology Faculty Publications

Whole-brain volumetric microscopy techniques such as serial two-photon tomography (STPT) can provide detailed information on the roles of neuroinflammation and neuroplasticity throughout the whole brain post-stroke. STPT automatically generates high-resolution images of coronal sections of the entire mouse brain that can be readily visualized in three dimensions. We developed a pipeline for whole brain image analysis that includes supervised machine learning (pixel-wise random forest models via the “ilastik” software package) followed by registration to a standardized 3-D atlas of the adult mouse brain (Common Coordinate Framework v3.0; Allen Institute for Brain Science). These procedures allow the detection of cellular fluorescent …

Interdependent Mechanisms Of Stress Susceptibility, Julie Elaine Finnell

Theses and Dissertations

Social stress is a significant risk factor for the emergence of psychiatric disorders including depression and anxiety. While there are a number of commercially available therapeutic options for the treatment of these disorders, these treatments require weeks of continuous use to produce behavioral efficacy. It has also been suggested that these traditional therapies are only marginally effective in producing complete remission, suggesting that our understanding as it pertains to the mechanisms underlying stressinduced behavioral dysfunction is still in its infancy. In the last few years, inflammation has become a major focus in the field of stress and depression as clinical …

Investigating Neuroinflammation And Demyelination In The Nervous System Of Twitcher Mice By The Use Of Immunohistochemistry, Irene Wilson

Natural Sciences and Mathematics | Biological Sciences Master's Theses

Neuroinflammation and demyelination are the hallmark lesions of the Twitcher mouse—the model of Krabbe Disease. By analyzing hemibrains and sciatic nerves via immunohistochemistry, we supported the microglial hypothesis that early activation of microglial cells, macrophages, and globoid cells in the nervous system of Twitcher mice results in specific cellular polarization states that may contribute to myelin loss. The influx of activated macrophages seen in both the central and peripheral nervous systems at days 21 and 17, respectively, accounted for this polarization. Using selected M1 and M2 markers, YKL-40, and GPNMB and CD206, respectively, we proved that microglial cells and macrophages …

A Proline Insertion-Deletion In The Spike Glycoprotein Fusion Peptide Of Mouse Hepatitis Virus Strongly Alters Neuropathology., Manmeet Singh, Abhinoy Kishore, Dibyajyoti Maity, Punnepalli Sunanda, Bankala Krishnarjuna, Sreeparna Vappala, Srinivasarao Raghothama, Lawrence C. Kenyon, Debnath Pal, Jayasri Das Sarma

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Fusion peptides (FPs) in spike proteins are key players mediating early events in cell-to-cell fusion, vital for intercellular viral spread. A proline residue located at the central FP region has often been suggested to have a distinctive role in this fusion event. The spike glycoprotein from strain RSA59 (PP) of mouse hepatitis virus (MHV) contains two central, consecutive prolines in the FP. Here, we report that deletion of one of these proline residues, resulting in RSA59 (P), significantly affected neural cell syncytia formation and viral titers postinfection in vitro. Transcranial inoculation of C57Bl/6 mice with RSA59 (PP) or RSA59 (P) …

Deletion Of P38Α Mapk In Microglia Blunts Trauma-Induced Inflammatory Responses In Mice, Josh M. Morganti, Danielle S. Goulding, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

Traumatic brain injury (TBI) is a significant cause of morbidity and mortality in the USA and other developed countries worldwide. Following the initial mechanical insult, the brain’s primary innate immune effector, microglia, initiate inflammatory signaling cascades and pathophysiological responses that can lead to chronic neuroinflammation and neurodegenerative sequelae. The p38α MAPK signaling pathway in microglia is a key contributor to inflammatory responses to diverse disease-relevant stressors and injury conditions. Therefore, we tested here whether microglia p38α contributes to acute and persistent inflammatory responses induced by a focal TBI. We generated conditional cell-specific knockout of p38α in microglia using a CX3CR1 …

The Effects Of Two Novel Anti-Inflammatory Compounds On Prepulse Inhibition And Neural Microglia Cell Activation In A Rodent Model Of Schizophrenia, Heath W. Shelton

Electronic Theses and Dissertations

Recent studies have shown elevated neuroinflammation in a large subset of individuals diagnosed with schizophrenia. A pro-inflammatory cytokine, tumor necrosis factor-alpha (TNFα), has been directly linked to this neuroinflammation. This study examined the effects of two TNFα modulators (PD2024 and PD340) produced by our collaborators at P2D Bioscience, Inc., to alleviate auditory sensorimotor gating deficits and reduce microglial cell activation present in the polyinosinic:polycytidylic (Poly I:C) rodent model of schizophrenia. Auditory sensorimotor gating was assessed using prepulse inhibition and microglial activation was examined and quantified using immunohistochemistry and confocal microscopy, respectively. Both PD2024 and PD340 alleviated auditory sensorimotor gating deficits …

Mammary Tumor And Mastectomy Synergistically Promote Neuroinflammation In A Breast Cancer Survivor Model, Kathryn M. Emmer, William H. Walker Ii, Ning Zhang, A. Courtney Devries

Clinical and Translational Science Institute

Understanding why breast cancer survivors are at an increased risk for cognitive and affective disorders is essential for developing targeted treatment plans and improving quality of life. Microglia priming results in chronic neuroinflammation and can contribute to neuronal degeneration and dysfunction, thereby offering a potential mechanism for altered brain function that persists after tumor removal. This study examined whether mammary tumors alter microglia and augment the inflammatory profile and behavior of mice. To test this, non-metastatic mammary tumor cells (67NR) were injected orthotopically into the mammary glands of BALB/c mice, allowed to grow for 16 days, and then the tumors …

Astrocytes Infected With Chlamydia Pneumoniae Demonstrate Altered Expression And Activity Of Secretases Involved In The Generation Of Β-Amyloid Found In Alzheimer Disease, Zein Al-Atrache, Danielle B Lopez, Susan Hingley, Denah Appelt

PCOM Scholarly Papers

BACKGROUND: Epidemiologic studies strongly suggest that the pathophysiology of late-onset Alzheimer disease (AD) versus early-onset AD has environmental rather than genetic causes, thus revealing potentially novel therapeutic targets to limit disease progression. Several studies supporting the "pathogen hypothesis" of AD demonstrate a strong association between pathogens and the production of β-amyloid, the pathologic hallmark of AD. Although the mechanism of pathogen-induced neurodegeneration of AD remains unclear, astrocytes, a key player of the CNS innate immune response and producer/metabolizer of β-amyloid, have been implicated. We hypothesized that Chlamydia pneumoniae infection of human astrocytes alters the expression of the amyloid precursor protein …

Green Tea Extract, Epigallocatechin Gallate, Protect Against Methamphetamine-Induced Striatal Neurotoxicity In Mice, Allen L. Pan

Dissertations, Theses, and Capstone Projects

Methamphetamine (METH) is a strong psychostimulant and its exposure can lead to serious neurological complications. METH-induced neuronal injury is the result of a complex interplay of different factors including dopamine (DA) overflow, oxidative stress and neuroinflammation. Although the mechanisms of METH-induced neurotoxicity have been extensively studied, there is still no effective therapeutic treatment. Therefore, it is essential to study potential drug candidates that can treat METH-induced neurotoxicity. Green tea extract, epigallocatechin gallate (EGCG), has emerged as a neuroprotective agent that can protect against several neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Recently, our lab has shown that EGCG prevents …

Editorial: Recent Advances In Psychiatry From Psycho-Neuro-Immunology Research: Autoimmune Encephalitis, Autoimmune Encephalopathy, And Mild Encephalitis, K. Bechter, D. Brown, S. Najjar

Journal Articles

No abstract provided.

Cholinergic Control Of Inflammation, Metabolic Dysfunction, And Cognitive Impairment In Obesity-Associated Disorders: Mechanisms And Novel Therapeutic Opportunities, E. H. Chang, S. S. Chavan, V. A. Pavlovh

Journal Articles

No abstract provided.

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 …

Gutting The Brain Of Inflammation: A Key Role Of Gut Microbiome In Human Umbilical Cord Blood Plasma Therapy In Parkinson's Disease Model, Jea-Young Lee, Julian P. Tuazon, Jared Ehrhart, Paul R. Sanberg, Cesar V. Borlongan

Neurosurgery and Brain Repair Faculty Publications

Current therapies for Parkinson's disease (PD), including L-3,4-dihydroxyphenylalanine (L-DOPA), and clinical trials investigating dopaminergic cell transplants, have generated mixed results with the eventual induction of dyskinetic side effects. Although human umbilical cord blood (hUCB) stem/progenitor cells present with no or minimal capacity of differentiation into mature dopaminergic neurons, their transplantation significantly attenuates parkinsonian symptoms likely via bystander effects, specifically stem cell graft-mediated secretion of growth factors, anti-inflammatory cytokines, or synaptic function altogether promoting brain repair. Recognizing this non-cell replacement mechanism, we examined here the effects of intravenously transplanted combination of hUCB-derived plasma into the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced rat model of PD. …

Immunomodulation With Human Umbilical Cord Blood Stem Cells Ameliorates Ischemic Brain Injury – A Brain Transcriptome Profiling Analysis, Maple L. Shiao, Ce Yuan, Andrew T. Crane, Joseph P. Voth, Mario Juliano, Laura L. Hocum Stone, Zhenghong Nan, Ying Zhang, Nicole Kuzmin-Nichols, Paul R. Sanberg, Andrew W. Grande, Walter C. Low

Neurosurgery and Brain Repair Faculty Publications

Our group previously demonstrated that administration of a CD34-negative fraction of human non- hematopoietic umbilical cord blood stem cells (UCBSC) 48 h after ischemic injury could reduce infarct volume by 50% as well as significantly ameliorate neurological deficits. In the present study, we explored possible mechanisms of action using next generation RNA sequencing to analyze the brain transcriptome profiles in rats with ischemic brain injury following UCBSC therapy. Two days after ischemic injury, rats were treated with UCBSC. Five days after administration, total brain mRNA was then extracted for RNAseq analysis using Illumina Hiseq 2000. We found 275 genes that …

Apoa-I Deficiency Increases Cortical Amyloid Deposition, Cerebral Amyloid Angiopathy, Cortical And Hippocampal Astrogliosis, And Amyloid-Associated Astrocyte Reactivity In App/Ps1 Mice, Emily B. Button, Guilaine K. Boyce, Anna Wilkinson, Sophie Stukas, Arooj Hayat, Jianjia Fan, Brennan J. Wadsworth, Jerome Robert, Kris M. Martens, Cheryl L. Wellington

Faculty & Staff Scholarship

Background

Alzheimer’s disease (AD) is defined by amyloid beta (Aβ) plaques and neurofibrillary tangles and characterized by neurodegeneration and memory loss. The majority of AD patients also have Aβ deposition in cerebral vessels known as cerebral amyloid angiopathy (CAA), microhemorrhages, and vascular co-morbidities, suggesting that cerebrovascular dysfunction contributes to AD etiology. Promoting cerebrovascular resilience may therefore be a promising therapeutic or preventative strategy for AD. Plasma high-density lipoproteins (HDL) have several vasoprotective functions and are associated with reduced AD risk in some epidemiological studies and with reduced Aβ deposition and Aβ-induced inflammation in 3D engineered human cerebral vessels. In mice, …

Polydatin Attenuates Neuronal Loss Via Reducing Neuroinflammation And Oxidative Stress In Rat Mcao Models, Fawad Ali Shah, Lina Al Kury, Tao Li, Alam Zeb, Phil Ok Koh, Fang Liu, Qiang Zhou, Ishtiaq Hussain, Arif Ullah Khan, Yuhua Jiang, Shupeng Li

All Works

Copyright © 2019 Shah, Kury, Li, Zeb, Koh, Liu, Zhou, Hussain, Khan, Jiang and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Ischemic stroke is characterized by permanent or transient obstruction of blood flow, which initiates a cascading pathological process, …

Plasma Neurofilament Light Chain And Amyloid-Β Are Associated With The Kynurenine Pathway Metabolites In Preclinical Alzheimer's Disease, Pratishtha Chatterjee, Henrik Zetterberg, Kathryn Goozee, Chai K. Lim, Kelly R. Jacobs, Nicholas J. Ashton, Abdul Hye, Steve Pedrini, Hamid R. Sohrabi, Tejal Shah, Prita R. Asih, Preeti Dave, Kaikai Shen, Kevin Taddei, David B. Lovejoy, Gilles J. Guillemin, Kaj Blennow, Ralph N. Martins

Research outputs 2014 to 2021

BACKGROUND: Blood markers indicative of neurodegeneration (neurofilament light chain; NFL), Alzheimer's disease amyloid pathology (amyloid-β; Aβ), and neuroinflammation (kynurenine pathway; KP metabolites) have been investigated independently in neurodegenerative diseases. However, the association of these markers of neurodegeneration and AD pathology with neuroinflammation has not been investigated previously. Therefore, the current study examined whether NFL and Aβ correlate with KP metabolites in elderly individuals to provide insight on the association between blood indicators of neurodegeneration and neuroinflammation.

METHODS: Correlations between KP metabolites, measured using liquid chromatography and gas chromatography coupled with mass spectrometry, and plasma NFL and Aβ concentrations, measured using …

Targeting The Blood-Brain Barrier To Prevent Sepsis-Associated Cognitive Impairment, Divine C. Nwafor, Allison L. Brichacek, Afroz S. Mohammad, Jessica Griffith, Brandon P. Lucke-Wold, Stanley A. Benkovic, Werner J. Geldenhuys, Paul R. Lockman, Candice M. Brown

Faculty & Staff Scholarship

Sepsis is a systemic inflammatory disease resulting from an infection. This disorder affects 750 000 people annually in the United States and has a 62% rehospitalization rate. Septic symptoms range from typical flu-like symptoms (eg, headache, fever) to a multifactorial syndrome known as sepsis-associated encephalopathy (SAE). Patients with SAE exhibit an acute altered mental status and often have higher mortality and morbidity. In addition, many sepsis survivors are also burdened with long-term cognitive impairment. The mechanisms through which sepsis initiates SAE and promotes long-term cognitive impairment in septic survivors are poorly understood. Due to its unique role as an interface …

The Role Of Suppressor Of Cytokine Signaling 3 In Neuroinflammatory Disease, Zhaoqi Yan

All ETDs from UAB

The Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) pathway plays a critical role in cytokine-mediated responses in both innate and adaptive immunity, and dysregulation of the JAK/STAT pathway is linked to many inflammatory disorders. Multiple Sclerosis (MS) is an inflammatory demyelinating disease that affects the central nervous system, and both innate and adaptive immunity are involved in disease progression. STAT3 signaling is critically involved in MS pathology and is negatively regulated by Suppressor Of Cytokine Signaling 3 (SOCS3). Both increased STAT3 activation and reduced SOCS3 expression are observed in immune cells from patients with MS. Although the role of …

Effects Of The Dual Orexin Receptor Antagonist Dora-22 On Sleep In 5xfad Mice, Marilyn J. Duncan, Hannah Farlow, Chairtra Tirumalaraju, Do-Hyun Yun, Chanung Wang, James A. Howard, Madison N. Sanden, Bruce F. O'Hara, Kristen J. Mcquerry, Adam D. Bachstetter

Neuroscience Faculty Publications

Introduction: Sleep disruption is a characteristic of Alzheimer's disease (AD) that may exacerbate disease progression. This study tested whether a dual orexin receptor antagonist (DORA) would enhance sleep and attenuate neuropathology, neuroinflammation, and cognitive deficits in an AD-relevant mouse model, 5XFAD.

Methods: Wild-type (C57Bl6/SJL) and 5XFAD mice received chronic treatment with vehicle or DORA-22. Piezoelectric recordings monitored sleep and spatial memory was assessed via spontaneous Y-maze alternations. Aβ plaques, Aβ levels, and neuroinflammatory markers were measured by immunohistochemistry, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction, respectively.

Results: In 5XFAD mice, DORA-22 significantly increased light-phase sleep without reducing Aβ levels, …

Role Of Sarm1 In Chronic Immune-Mediated Central Nervous System Inflammation, Kenneth E. Viar Ii

Theses and Dissertations

SARM1 is an injury-induced nicotinamide adenine dinucleotide nucleosidase (NADase) that was previously shown to promote axonal degeneration in response to traumatic, toxic, and excitotoxic stressors. This raises the question of whether a SARM1-dependent program of axonal degeneration is central to a common pathway contributing to disease burden in neurological disorders. The degree to and mechanism by which SARM1 inactivation decreases the pathophysiology of such disorders is of interest to establish the rationale to pursue SARM1 as a therapeutic target. In this study, we compare the course and pathology of experimental autoimmune encephalomyelitis (EAE) in Sarm1-knockout (KO) mice and wild-type …