Neuroscience and Neurobiology Commons^™

Allosteric Modulatory Effects Of Sri-20041 And Sri-30827 On Cocaine And Hiv-1 Tat Protein Binding To Human Dopamine Transporter, Wei-Lun Sun, Pamela M. Quizon, Yaxia Yuan, Wei Zhang, Subramaniam Ananthan, Chang-Guo Zhan, Jun Zhu

Molecular Modeling and Biopharmaceutical Center Faculty Publications

Dopamine transporter (DAT) is the target of cocaine and HIV-1 transactivator of transcription (Tat) protein. Identifying allosteric modulatory molecules with potential attenuation of cocaine and Tat binding to DAT are of great scientific and clinical interest. We demonstrated that tyrosine 470 and 88 act as functional recognition residues in human DAT (hDAT) for Tat-induced inhibition of DA transport and transporter conformational transitions. Here we investigated the allosteric modulatory effects of two allosteric ligands, SRI-20041 and SRI-30827 on cocaine binding on wild type (WT) hDAT, Y470 H and Y88 F mutants. Effect of SRI-30827 on Tat-induced inhibition of [³H]WIN35,428 …

Rod-Shaped Microglia Morphology Is Associated With Aging In 2 Human Autopsy Series, Adam D. Bachstetter, Eseosa T. Ighodaro, Yasmin Hassoun, Danah Aldeiri, Janna H. Neltner, Ela Patel, Erin L. Abner, Peter T. Nelson

Spinal Cord and Brain Injury Research Center Faculty Publications

A subtype of microglia is defined by the morphological appearance of the cells as rod-shaped. Little is known about this intriguing cell type, as there are only a few case reports describing rod-shaped microglia in the neuropathological literature. Rod-shaped microglia were shown recently to account for a substantial proportion of the microglia cells in the hippocampus of both demented and cognitively intact aged individuals. We hypothesized that aging could be a defining feature in the occurrence of rod-shaped microglia. To test this hypothesis, two independent series of autopsy cases (total n=168 cases), which covered the adult lifespan from 20 – …

Ck2—An Emerging Target For Neurological And Psychiatric Disorders, Julia Castello, Andre Ragnauth, Eitan Friedman, Heike Rebholz

Publications and Research

Protein kinase CK2 has received a surge of attention in recent years due to the evidence of its overexpression in a variety of solid tumors and multiple myelomas as well as its participation in cell survival pathways. CK2 is also upregulated in the most prevalent and aggressive cancer of brain tissue, glioblastoma multiforme, and in preclinical models, pharmacological inhibition of the kinase has proven successful in reducing tumor size and animal mortality. CK2 is highly expressed in the mammalian brain and has many bona fide substrates that are crucial in neuronal or glial homeostasis and signaling processes across synapses. Full …

4-Nonylphenol Induces Neurodegeneration By Altering Cytoskeleton, Cynthia Carreon

Open Access Theses & Dissertations

4-nonylphenol (4-NP), an endocrine-disrupting compound (EDC), has been shown to affect brain development and may cause neurodegeneration. In the environment, 4-NP arises as a degradation product of alkylphenol polyethoxylates, compounds widely used as nonionic surfactants in commercial production, as well as in herbicides, pesticides, polystyrene plastics, and paints and has been shown to undergo a high level of accumulation in biological tissues. However, the mechanism by which 4-NP exerts its effect is not understood. Recent results from our laboratory indicate that Gβγ, an important component of the G protein-signaling pathway, induces neuronal outgrowth and differentiation by modulating microtubule (MT) assembly, …

Mitogen And Morphogen Signaling Dysregulation: Pathophysiological Influence In Pancreatic Cancer And Alzheimer’S Disease, Eric Cruz

Theses & Dissertations

Although the etiology of a particular disease will vary, there are genetic and epigenetic bottlenecks that frequently converge resulting in dysregulation of mitogenic and morphogenetic signaling. This propensity is acutely experienced in malignancy and neurodegenerative disease.

Here, we have first investigated the role of dysregulated signaling in the context of pancreatic cancer (PC). Morphogenetic signaling has been regarded as a pleiotropic pathway with the potential to promote and inhibit metastatic features. Our investigation of bone morphogenetic protein 2 (BMP-2), an archetypical member of the BMP superfamily, has revealed the presence of extracellular, intracellular, and long non-coding RNA products. Our findings …

Voltage-Gated K+ Channels And Hiv-1-Induced Neural Injury: Implications For Pathogenesis Of Hiv-1-Associated Neurocognitive Disorders, Han Liu

Theses & Dissertations

Human immunodeficiency virus-1 (HIV-1)-associated neurocognitive disorder (HAND) is a subcortical disease involving neuronal loss and myelin damage. Myelin is deposited by oligodendrocytes through a complex process including oligodendrocyte progenitor cell (OPC) proliferation and maturation. Oligodendrocytes/OPCs are susceptible to viral proteins such as Tat and that myelin damage is associated with oligodendrocyte number decrease. It has been shown that activation of voltage-gated K⁺ (K_V) channels mediates apoptosis in various cell types. K_V1.3 is the most predominant K_V channel expressed in OPCs/oligodendrocytes and potentially involved in OPC developmental regulation. We studied the involvement of K_{V …}

Effect Of Cntf Derived Peptide, P021 On Cognition And Pathology In 3xtg-Ad Mouse Model Of Alzheimer's Disease, Narjes Baazaoui

Dissertations, Theses, and Capstone Projects

Studies described in this thesis deal with the preventive effects of a neurogenic/neurotropic peptidergic compound, P021, on neurogenesis and synaptic deficits, neurodegeneration, cognitive impairment, and Ab and tau pathologies in a 3xTg-AD mouse model of Alzheimer’s disease (AD).

Background: AD is a chronic progressive neurodegenerative disease. Its multifactorial nature and the heterogeneity make its treatment especially challenging. Although it is a major burden in society, at present there is no drug that can stop or slow down the progression of the disease. Currently, the only available treatments are symptomatic and for mild to severe stages. The development of a drug …

Activation Of Target Gene Expression In Neurons By The C. Elegans Rfx Transcription Factor, Daf-19, Katherine P. Mueller

Lawrence University Honors Projects

DAF-19, the only RFX transcription factor found in C. elegans, is required for the formation of neuronal sensory cilia. Four isoforms of the DAF-19 protein have been reported, and the m86 nonsense (null) mutation affecting all four isoforms has been shown to prevent cilia formation. Transcriptome analyses employing microarrays of L1 and adult stage worms were completed using RNA from daf-19(m86) worms and an isogenic wild type strain to identify additional putative DAF-19 target genes. Using transcriptional fusions with GFP, we compared the expression patterns of several potential gene targets using fluorescence confocal microscopy. Expression patterns were characterized in …

The Role Of Daf-19 In Non-Ciliated Neurons: How Is Neural Development Regulated By Different Daf-19 Isoforms?, Zabdiel Ek Vazquez

Lawrence University Honors Projects

A degenerative disease-like phenotype, specifically reduction in synaptic protein levels in adult worms, is correlated with loss-of-function of the only RFX transcription factor gene, daf-19, in C. elegans. This gene encodes four known transcription factor isoforms, two of which are correlated with particular functions. The DAF-19C isoform activates genes responsible for cilia development, while DAF-19M is needed for cilia specification in males. A comparison of the transcriptome of daf-19 null and isogenic wild type adult worms suggests both positive and negative regulation of gene expression is correlated with the presence of DAF-19 proteins. We have assessed DAF-19 regulation …

Neuroprotection Comparison Of Different Nutraceutical Compounds Against Mechanistically Distinct Cell Death Inducing Agents, Faten I. Taram

Electronic Theses and Dissertations

Neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), include the progressive loss of structure and function of neurons leading to neuronal death. All of these diseases are fatal, as there is no cure for them. The causes of these diseases are unknown; however, there are many proposed mechanisms that lead to neurodegenerative diseases. Oxidative stress is the leading cause of cell death in neurodegenerative diseases, in addition to other mechanisms including endoplasmic reticulum stress, proteasome inhibition, nitrosative stress, inflammation and excitotoxicity. More understanding of the death mechanisms at work in neurodegeneration is necessary to …

The Neuroprotective And Therapeutic Effects Of Anthocyanins And Their Metabolites In Vitro And In A Mouse Model Of Amyotrophic Lateral Sclerosis, Aimee Nicole Winter

Electronic Theses and Dissertations

Anthocyanins, a unique class of flavonoid compounds, have recently come to the forefront of investigative research aimed at evaluating the potential applications of natural products to human health. Evidence demonstrating the beneficial effects of anthocyanin consumption has been reported for a myriad of conditions including cancer, cardiovascular disease, and lately, neurodegenerative disease. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS) are characterized by the death of specific neuronal populations within the brain and spinal cord, leading to cognitive and/or motor impairment. While the etiology of many of these diseases is largely unknown, several factors have …

Development Of Manganese-Enhanced Magnetic Resonance Imaging (Memri) Methods To Study Pathophysiology Underlying Neurodegenerative Diseases In Murine Models, Aditya N. Bade

Theses & Dissertations

Manganese-enhanced magnetic resonance imaging (MEMRI) opens the great opportunity to study complex paradigms of central nervous system (CNS) in freely behaving animals and reveals new pathophysiological information that might be otherwise difficult to gain. Due to advantageous chemical and biological properties of manganese (Mn²⁺), MEMRI has been successfully applied in the studies of several neurological diseases using translational animal models to assess comprehensive information about neuronal activity, morphology, neuronal tracts, and rate of axonal transport. Although previous studies highlight the potential of MEMRI for brain imaging, the limitations concerning the use of Mn²⁺ in living animals and …

Disease-Related Microglia Heterogeneity In The Hippocampus Of Alzheimer's Disease, Dementia With Lewy Bodies, And Hippocampal Sclerosis Of Aging, Adam D. Bachstetter, Linda J. Van Eldik, Frederick A. Schmitt, Janna H. Neltner, Eseosa T. Ighodaro, Scott J. Webster, Ela Patel, Erin L. Abner, Richard J. Kryscio, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

Introduction: Neuropathological, genetic, and biochemical studies have provided support for the hypothesis that microglia participate in Alzheimer's disease (AD) pathogenesis. Despite the extensive characterization of AD microglia, there are still many unanswered questions, and little is known about microglial morphology in other common forms of age-related dementia: particularly, dementia with Lewy bodies (DLB) and hippocampal sclerosis of aging (HS-Aging). In addition, no prior studies have attempted to compare and contrast the microglia morphology in the hippocampus of various neurodegenerative conditions.

Results: Here we studied cases with pathologically-confirmed AD (n = 7), HS-Aging (n = 7), AD + HS-aging …

Death Associated Protein Kinase (Dapk) -Mediated Neurodegenerative Mechanisms In Nematode Excitotoxicity, John S. Del Rosario, Katherine Genevieve Feldmann, Towfiq Ahmed, Uzair Amjad, Bakkeung Ko, Junhyung An, Tauhid Mahmud, Maha Salama, Shirley Mei, Daniel Asemota, Itzhak Mano

Publications and Research

Background: Excitotoxicity (the toxic overstimulation of neurons by the excitatory transmitter Glutamate) is a central process in widespread neurodegenerative conditions such as brain ischemia and chronic neurological diseases. Many mechanisms have been suggested to mediate excitotoxicity, but their significance across diverse excitotoxic scenarios remains unclear. Death Associated Protein Kinase (DAPK), a critical molecular switch that controls a range of key signaling and cell death pathways, has been suggested to have an important role in excitotoxicity. However, the molecular mechanism by which DAPK exerts its effect is controversial. A few distinct mechanisms have been suggested by single (sometimes contradicting) studies, and …

Neuroinflammation And J2 Prostaglandins: Linking Impairment Of The Ubiquitin-Proteasome Pathway And Mitochondria To Neurodegeneration, Maria E. Figueiredo-Pereira, Patricia Rockwell, Thomas Schmidt-Glenewinkel, Peter Serrano

Publications and Research

The immune response of the CNS is a defense mechanism activated upon injury to initiate repair mechanisms while chronic over-activation of the CNS immune system (termed neuroinflammation) may exacerbate injury. The latter is implicated in a variety of neurological and neurodegenerative disorders such as Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, HIV dementia, and prion diseases. Cyclooxygenases (COX-1 and COX-2), which are key enzymes in the conversion of arachidonic acid into bioactive prostanoids, play a central role in the inflammatory cascade. J2 prostaglandins are endogenous toxic products of cyclooxygenases, and because their levels are significantly …

Suppression Of Neurodegenerative Symptoms Via Suppressor Of Levy Mutation In Drosophila Melanogaster, William Kaputa

Forensic Science Theses

Mutation of the levy gene on chromosome 2 of Drosophila melanogaster has previously been shown to cause temperature-induced paralysis and neurodegeneration. The Suppressor of levy mutation, Su(levy), also on chromosome 2, modulates the effects of the levy mutation and partly rescues the wild-type phenotype. The goal of this research was to determine if Su(levy) mutation alleviates the effects of neurodegeneration caused by mutations associated with Alzheimer’s and Parkinson’s diseases in humans. The mutant genes used were hLRRK2, α-Synuclein, DJ1-α, Pink, Parkin, and Aβ-42. To determine this, flies carrying the above-mentioned mutant genes were …

A Comprehensive Study Of The Effects Of Neurotoxins On Noradrenergic Phenotypes, Neuronal Responses And Potential Intervention By Antidepressants In Noradrenergic Cells, Yan Wang

Electronic Theses and Dissertations

It has been reported that locus coeruleus (LC) degeneration precedes the degeneration of other neurons in the brain in some neurodegenerative diseases like Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, the precise mechanisms of neurodegeneration remain to be elucidated. N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) has been widely used as a noradrenergic neurotoxin in the development of AD and PD animal models for specific LC degeneration. However, the precise mechanism of action of DSP4 remains unclear. An increased systemic DNA damage caused by neurotoxin or oxidative stress has been found to be related to the pathogenic development of neurodegeneration. The process of neurodegeneration …

The Role Of The Striatal Neuropeptide Neurotensin In The Methamphetamine-Induced Neural Injury In Mice, Qingkun Liu

Dissertations, Theses, and Capstone Projects

Methamphetamine (METH) is a widely abused psychostimulant that induces neurotoxicity to several brain regions, including the striatum. Similar to dopamine (DA) in chemical structure, METH can be transported into DA pre-synaptic terminals, evoking the neurodegeneration in DA terminals and post-synaptic striatal neurons. Despite the critical role of DA in METH-induced neurodegeneration, no pharmaceutical therapeutics has been approved for these conditions. It is therefore essential to investigate the endogenous factors regulating the dopaminergic system. The neuropeptide neurotensin has emerged as a potential modulator of METH-induced striatal neurodegeneration mainly due to its intimate interactions with dopamine in the striatum.

In this study, …

Neuroinflammation And Neurodegeneration In Adult Rat Brain From Binge Ethanol Exposure: Abrogation By Docosahexaenoic Acid, Nuzhath Tajuddin, Kwan-Hoon Moon, Simon Alex Marshall, Kimberly Nixon, Edward J. Neafsey, Hee-Yong Kim, Michael A. Collins

Pharmaceutical Sciences Faculty Publications

Evidence that brain edema and aquaporin-4 (AQP4) water channels have roles in experimental binge ethanol-induced neurodegeneration has stimulated interest in swelling/edema-linked neuroinflammatory pathways leading to oxidative stress. We report here that neurotoxic binge ethanol exposure produces comparable significant effects in vivo and in vitro on adult rat brain levels of AQP4 as well as neuroinflammation-linked enzymes: key phospholipase A2 (PLA2) family members and poly (ADP-ribose) polymerase-1 (PARP-1). In adult male rats, repetitive ethanol intoxication (3 gavages/d for 4 d, ∼ 9 g/kg/d, achieving blood ethanol levels ∼ 375 mg/dl; "Majchrowicz" model) significantly increased AQP4, Ca+2-dependent PLA2 GIVA (cPLA2), phospho-cPLA2 GIVA …

Gbetagamma-Microtubule Mediated Mechanism Of Neuronal Differentiation, Jorge Anibal Sierra Fonseca

Open Access Theses & Dissertations

Neurodegeneration, a progressive loss of nerve cells (neurons), occurs in many neurological disorders, including Alzheimer's and Parkinson's diseases, as well as in the aging brain. Disruption of microtubules in neurons and the aggregation of proteins associated with them is the hallmark of neurodegeneration. Nevertheless, the cause of this disorder is largely unknown, and no effective drugs are available to treat the disease processes. Therefore, there is a need to understand the molecular mechanisms that drive the assembly and disassembly of microtubules during neurite outgrowth and differentiation. Evidence suggests that nerve growth factor (NGF) induces neurite outgrowth from PC12 cells by …

Inhibitors Of Polyisoprenylated Methylated Protein Methyl Esterase (Pmpmease) Cause Neurodegeneration By Altering Microtubules And Gβγ In Pc12 Cells, Jose A. Rivas Jr., Rebekah M. Bach, Jessica Martinez-Jurado, Jorge A. Siera-Fonseca, Sukla Roychowdhury

COURI Symposium Abstracts, Summer 2012

Neurodegeneration, a progressive loss of nerve cells (neurons), occurs in many neurological disorders including Alzheimer’s disease, Parkinson’s disease, Schizophrenia and drug addiction. Disruption of Microtubules (MTs), a major component of cytoskeleton and aggregation of proteins associated with them is the hallmark of neurodegeneration. Gβγ, an important component of G protein signaling has been shown to induce neurite outgrowth of PC12 cells by interacting with microtubules. The goal of the present study is to understand whether interfering with Gβγ-MT mediated pathway causes neurodegeneration. Because prenylation of γ subunits is important for the interaction of Gβγ with MTs, we used inhibitors (L-23 …

Gβγ-Microtubule Interaction And Neurodegeneration, Jane K. Martinez, Jorge Sierra, Sukla Roychowdhury Ph.D.

COURI Symposium Abstracts, Summer 2012

Aberrant organization of microtubules (MTs) is known to be a feature of neurodegeneration, which occurs in many neurological disorder including Alzheimer’s disease, Parkinson’s disease, neuropsychiatric illness such as schizophrenia, and drug addiction. Previously, Gβγ, an important component of G protein-coupled signaling pathways, has been shown to regulate neurite outgrowth by interacting with MTs. The aim of the present study is to understand the Gβγ regulation of MT assembly and its relation to neurodegeneration, using GRK-ct peptide (consists of the carboxy terminus of G protein-coupled-receptor kinase) which is known to inhibit Gβγ-dependent signaling by binding to and sequestering Gβγ. PC12 cells …

Upregulation Of Reactive Oxygen Species During The Retrovirus Life Cycle And Their Roles In A Mutant Of Moloney Murine Leukemia Virus, Ts1-Mediated Neurodegeneration, Soo Jin Kim

Dissertations and Theses (Open Access)

Viral invasion of the central nervous system (CNS) and development of neurological symptoms is a characteristic of many retroviruses. The mechanism by which retrovirus infection causes neurological dysfunction has yet to be fully elucidated. Given the complexity of the retrovirus-mediated neuropathogenesis, studies using small animal models are extremely valuable. Our laboratory has used a mutant moloney murine leukemia retrovirus, ts1-mediated neurodegneration. We hypothesize that astrocytes play an important role in ts1-induced neurodegeneration since they are retroviral reservoirs and supporting cells for neurons. It has been shown that ts1 is able to infect astrocytes in vivo and in …

Differential Levels Of Glutamate Dehydrogenase 1 (Glud1) In Balb/C And C57bl/6 Mice And The Effects Of Overexpression Of The Glud1 Gene On Glutamate Release In Striatum, Kevin N. Hascup, Xiaodong Bao, Erin R. Hascup, Dongwei Hui, Wenhao Xu, Francois Pomerleau, Peter Huettl, Mary L. Michaelis, Elias K. Michaelis, Greg A. Gerhardt

Neuroscience Faculty Publications

We have previously shown that overexpression of the Glud1 (glutamate dehydrogenase 1) gene in neurons of C57BL/6 mice results in increased depolarization-induced glutamate release that eventually leads to selective neuronal injury and cell loss by 12 months of age. However, it is known that isogenic lines of Tg (transgenic) mice produced through back-crossing with one strain may differ in their phenotypic characteristics from those produced using another inbred mouse strain. Therefore, we decided to introduce the Glud1 transgene into the Balb/c strain that has endogenously lower levels of GLUD1 (glutamate dehydrogenase 1) enzyme activity in the brain as compared with …

Functional Properties Of L-Glutamate Regulation In Anesthetized And Freely Moving Mice, Kevin N. Hascup

Theses and Dissertations--Neuroscience

L-glutamate (Glu) is the predominant excitatory neurotransmitter in the mammalian central nervous system with involvement encompassing learning and memory, cognition, plasticity, and motor movement. Dysregulation of the glutamatergic system is implicated in several neurological disorders including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and amyotrophic lateral sclerosis. The mechanisms underlying these neurological disorders are not clear, but evidence suggests that abnormal Glu neurotransmission plays a role. Elevated levels of Glu in the synaptic cleft overstimulate the N-methyl-Daspartate receptor leading to excitotoxicity, which causes neuronal loss in chronic neurological diseases. What is less understood is the source for the elevated Glu levels. …