Neuroscience and Neurobiology Commons^™

The Rpm-1/Phr Signaling Hub Modulates Tau-Induced Neurodegeneration Through Regulation Of Microtubule Stability And Mapk Pathways In C. Elegans, Xinxing Ding

Theses and Dissertations

Neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia, are characterized by the accumulation of pathological tau proteins and progressive neuronal loss. Although research regarding tau-mediated toxicity is extensive, the specific pathology that determine whether neurons maintain homeostasis or succumb to collapse under tau-induced stress remain incompletely elucidated. A central, yet still insufficiently understood, feature of these diseases is the disruption of the microtubule (MT) cytoskeleton . The PHR protein family is evolutionarily highly conserved; within this family, RPM-1 in C. elegans functions as an intracellular signaling hub that regulates axon development, synapse formation, axon termination, and various microtubule-associated processes. This …

Survivin And Caspases Coordinate Proteolytic Cleavage Of The Saga Chromatin Modifying Complex, Elinor Harrison, Alejandro Damian, Cj Talton

Medical Student Research Symposium

Title: Survivin and Caspases Coordinate Proteolytic Cleavage of the SAGA Chromatin Modifying Complex

Elinor Harrison¹, Alejandro Damian¹, CJ Talton¹, Jelly H Soffers¹, Abudu I Bello¹, Kara M Costanzo¹, Joe Bean¹, Ryan D Mohan¹

¹Wayne State University School of Medicine

Background: The Spt Ada Gcn5 Acetyltransferase (SAGA) chromatin modifying complex is a critical regulator of gene expression. Mutation or stoichiometric imbalance of SAGA subunits leads to a spectrum of diseases in model organisms and in humans, including neurodegeneration. SAGA contributes to gene activation through coordinated …

Exposure To Manganese During Juvenile Development Increases Microglial Activation In The Hippocampus Following Systemic Infection With A/California/04/2009 Influenza A H1n1 Virus, Megan Hager, Adam Schuller, Omar Yanouri, Collin Bantle, Richard Smeyne, Ronald Tjalkens

Farber Institute for Neuroscience Faculty Papers

Up to 80% of patients with Parkinson’s Disease (PD) develop dementia within 20 years of diagnosis. Although the etiology of PD and related neurodegenerative disorders is poorly understood, risk factors including environmental toxicants and viral infections are linked to disease onset and progression. Exposure to high doses of the essential element, manganese (Mn), causes neurotoxicity associated with parkinsonian symptoms and cognitive impairment in humans. Additionally, epidemiologic studies indicate that viral infections increase risk of developing PD. Previously, our lab demonstrated that mice exposed to Mn during juvenile development showed greater neuroinflammatory changes in microglia within the substantia nigra following systemic …

Disrupted Nuclear Function And Nucleocytoplasmic Transport In Parkinson’S Disease, Ichiro M. Matoba

The Cardinal Edge

No abstract provided.

Investigating The Effects Of Nucleopore Defects On The Cellular Response To Stress In Als/Ftd Ipsc-Derived Neurons, Alicia Christine Collins

Open Access Dissertations

Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) is a progressive neurodegenerative disease spectrum characterized by motor dysfunction, cognitive decline, and death within a few years of clinical onset. Hallmark features of ALS/FTD include defects in nucleocytoplasmic transport (NCT) and abnormal cytoplasmic mislocalization and aggregation of the RNA-binding protein TDP-43, both of which have been shown to be exasperated by oxidative stress (OS). It remains unclear how these processes are connected and how they collectively contribute to neurodegeneration. To fill this gap of knowledge, we used human embryonic kidney cells, neuroblastoma cells, and induced pluripotent stem cell-derived cortical neurons harboring the ALS/FTD C9ORF72 …

A Single Center Study Of The Symbol Digit Modalities Test As A Screening Tool For Cognitive Impairment In Parkinson’S Disease, Daniyell Thomason, Morganne Manuel, Shannin Moody, Jesus Lovera, Brain Copeland, Deidre Devier

School of Medicine Faculty Publications

Background: Parkinson’s Disease (PD) can include physical signs and possibly cognitive impairment, resulting from the convergence of pathologicalprocesses involving dopaminergic dysfunction, accumulation ofalpha-synuclein, cholinergic deficits, and disruption of otherneurotransmitter systems. We used screening tests to evaluate thecharacteristics of cognitive performance in patients with PD and to assess their validity compared tothe Montreal Cognitive Assessment (MoCA). Methods: This is a natural history study of participants with PD and controls screened for possible cognitive impairment using the MoCA, Symbol Digit Modalities Test (SDMT), and King-Devick (KD). The groups were compared on performance and then factors associated with cognitive performance (age, diagnosis, and …

Mechanistic Insights Into The Neuroprotective Effects Of The Antidepressant Agomelatine In Alzheimer's Disease, Grace Terry

Dissertations, Theses, and Capstone Projects

Alzheimer’s Disease (AD) is a complex neurodegenerative disease that has limited treatment options and no cure. AD is characterized by robust pathology including extracellular amyloid beta plaques, intracellular neurofibrillary tangles, neuronal and synaptic loss, neuroinflammation, and brain atrophy. AD presents with cognitive decline and memory loss but only years after neuropathology has started to accumulate. This robust pathology has made AD difficult to treat and highlights the need for therapeutics that modulate multiple pathways. Agomelatine (AGO) was selected by a high-throughput machine learning drug repurposing algorithm by our collaborator Dr. Lie Xie (Hunter College Dept. of Comp. Sci.) as having …

Structural Functional Investigation Of Hap40, Amanda M. Solbach

Dissertations and Theses (Open Access)

STRUCTURAL FUNCTIONAL INVESTIGATION OF HAP40

Amanda Marie Solbach

Dissertation Advisor: Sheng Zhang, Ph.D.

Huntington’s disease (HD) is a devastating neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the Huntingtin (HTT) gene, resulting in a mutant huntingtin (mHTT) protein with an elongated polyglutamine tract. While the genetic basis of HD is well established, the mechanisms underlying mHTT toxicity and its impact on cellular function remain incompletely understood. Recent discoveries implicate Huntingtin-associated protein 40 (HAP40) as a critical regulator of HTT stability and intracellular function. However, the physiological and pathological significance of this interaction has not been fully explored.

This …

Alpha-Synuclein Null Mutation Exacerbates The Phenotype Of A Model Of Menkes Disease In Female Mice, Meganne Casey, Dan Zou, Renee Reijo Pera Phd, Tiffany Hensley-Mcbain, Deborah E. Cabin

Touro College of Osteopathic Medicine (Great Falls) Publications and Research

Human SNCA, which encodes a-synuclein protein (SNCA), was the first gene linked to familial Parkinson's disease (PD). Since the discovery of the genetic link of SNCA to Parkinson's nearly three decades ago, many studies have investigated the normal function of SNCA protein. However, understanding of the normal function of SNCA is complicated by the lack of a reliable mammalian model of PD; indeed, mice with homozygous null mutations in the Snca gene live a normal lifespan and have only subtle synaptic deficits. Here, we report the first genetic modifier (a sensitized mutation) of a murine Snca null …

Neurodegenerative Disease Mechanisms: Mitochondrial Impairment, Tau Aggregation, And Neuroinflammation As Central Drivers Of Disease Progression, Luis D. Estrella

Theses & Dissertations

The study of the intricate molecular mechanisms behind the pathology of neurodegenerative diseases has become a primary research area in the past decades. The major branches of these studies involve both disease progression and disease pathogenesis, in which neuroscientists have studied, and continue to study, the role that mitochondrial dysfunction, aberrant protein aggregation (like Tau), and immune cell reactions have on these. However, more recent studies have shined light to the fact that these three pathological features are not independent from one another and that their synchronous contributions may be the ultimate driver of neurodegeneration. This dissertation encompasses four different …

From Dysbiosis To Dysfunction: Investigating The Effects Of Chronic Cocaine Use On Oral Microbial Shifts And Neuropathogenesis, Douglas E. Johnson

MUSC Theses and Dissertations

Cocaine use disorder remains a significant public health challenge. However, the mechanisms by which chronic cocaine use contributes to neuroinflammation and cognitive decline are still not fully understood. Chronic non-intravenous cocaine use is associated with oral microbial dysbiosis. Although the gut-brain axis has been widely studied, the impact of cocaine-mediated shifts on the oral microbiome on systemic and neuroinflammation remains a significant yet largely unexplored gap. This dissertation investigates the hypothesis that cocaine-specifically enriched oral Streptococcus parasanguinis triggers neuroinflammation, neuropathology, and cognitive deficits. In a human study, the saliva microbiomes from chronic cocaine users exhibited reduced α-diversity, enriched Streptococcus genus, …

Investigating The Role Of Fnci-1 In The Development And Function Of The C. Elegans Nervous System, Meagan Collins

Open Access Master's Theses

Fanconi Anemia (FA) is a rare human genetic disease caused by mutation of any of twenty-three genes on the FA pathway, which functions in the repair of DNA damage and the maintenance of genome stability. FA is clinically characterized by congenital abnormalities and a predisposition to aplastic anemia and malignancies. Recently, progressive neurological symptoms and abnormal neurological findings on imaging have been noted in FA patients, including cerebral and cerebellar lesions, calcification, necrosis, gliosis, and associated acute and chronic neurological symptoms; this constellation of symptoms has been termed Fanconi Anemia-Associated Neurological Syndrome (FANS).

To elucidate the molecular etiology of FANS, …

Blood Biomarkers In Down Syndrome: Facilitating Alzheimer’S Disease Detection And Monitoring, Melissa E. Petersen, Lisi Flores-Aguilar, Elizabeth Head, Laia Montoliu-Gaya, Andre Strydom, Sarah E. Pape, Juan Fortea, Nicholas J. Ashton, Chinedu Udeh-Momoh, Sid E. O’Bryant, Dwight German, Florin Despa, Mark Mapstone, Henrik Zetterberg

Neurology Faculty Publications

Blood-based biomarkers continue to be explored for disease detection, monitoring of progression, and therapeutic outcomes as the diagnostic determination of Alzheimer’s Disease in Down Syndrome (DS-AD) remains challenging in clinical settings. This perspective highlights the current status of this effort. Overall, amyloid (A), tau (T), and neurodegeneration (AT[N]) blood-based biomarkers have been shown to increase with disease pathology for individuals with DS. Phosphorylated tau biomarkers (p-tau217, p-tau181) have been consistently shown to track disease progression for DS-AD and are likely good candidates for use in clinical settings. Biomarkers of inflammation (glial fibrillary acidic protein) also show promise; however, additional work …

Therapeutic Potential Of Astrocyte-Derived Extracellular Vesicles In Mitigating Cytotoxicity And Transcriptome Changes In Human Brain Endothelial Cells, Ruth Juliana Stewart

Doctoral Dissertations

Extracellular vesicles (EVs) play a major role in cell-to-cell communication via the horizontal transfer of RNA, DNA, proteins, and lipids that affect the physiological response of the recipient cells. Astrocytes are a type of glial cell that exerts a protective effect on neurons and brain endothelial cells. The astrocytes and the endothelial cells form the blood-brain barrier. Due to their nano-size and non-complex structure, EVs can efficiently cross the blood-brain barrier. This study investigated and assessed the impact of EVs on reducing oxidative DNA damage in human brain endothelial cells (HBECs). The protective potential of astrocyte-derived EVs was determined by …

Early Onset Alzheimer’S Disease Markers In Mouse Hippocampus Unveiled By Single-Cell Transcriptomic Analysis Following Cranial Radiotherapy, Tuba Aksoy

Dissertations and Theses (Open Access)

Cranial radiation therapy plays an integral role in the treatment of brain tumors but can lead to progressive cognitive deficits in survivors by mechanisms that are poorly understood. To develop preventive or mitigative strategies, it is crucial to better understand the underlying pathogenesis of radiation-induced cognitive impairments. The study investigated single-cell transcriptomics and DNA methylation changes as potential drivers of persistent cellular dysfunction after radiation exposure, specifically concentrating on the CA1-3 regions of the hippocampus and the prefrontal cortex due to their role in cognitive functions. Thirteen-week-old mice underwent whole-brain radiation at clinically relevant doses. Following whole-brain radiation, an assessment …

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 …

Inflammaging In The Alzheimer’S Brain And Beyond: Insights From A Transgenic Mouse Model On The Sex-Specific Pathophysiology Of Alzheimer’S Disease, Alicia Jeanne Barber

Dartmouth College Ph.D Dissertations

Aging and sex are major risk factors for developing late-onset Alzheimer’s disease. Compared to men, women experience worse neuropathological burden and cognitive decline despite living longer with the disease. Similarly, male 3xTg-AD mice, developed to model Alzheimer’s disease, no longer consistently exhibit standard Alzheimer’s neuropathology yet experience higher rates of mortality - providing a unique opportunity to further elucidate this dichotomy. We hypothesized that sex differences in the biological aging process yield distinct pathological and molecular Alzheimer’s disease signatures in males and females, which could be harnessed for therapeutic and biomarker development.

We aged male and female, 3xTg-AD and B6129 …

Effects Of Aerobic Exercise On Rage And Lrp1 In Stz And Hfd Models Of Diabetes: Relationship With Cognitive Function And Aβ Clearance, Corey Joseph Frank

Legacy Theses & Dissertations (2009 - 2024)

The number of individuals with diabetes worldwide has quadrupled since 1980, making diabetes the 4th most common cause of death from non-communicable disease. Since 1975, the number of individuals classified as obese has tripled to 650 million adults, or 13% of the global population (World Health Organization, 2018). Obesity rates in the United States are three times the global average, with 39.8% of adults having a body-mass index of 30 or greater (Hales, 2017). At the same time, in the United States, AD is the sixth most common cause of death, with 5.8 million currently diagnosed, a number that may …

A Multi-Modal Imaging Analysis Of Inter-Community Hub Nodes In Subjective Cognitive Decline Linking Longitudinal Hub Function Disruption To White Matter Integrity Kurtosis, Duncan Nowling

MUSC Theses and Dissertations

Subjective Cognitive Decline (SCD) has garnered much interest as a potential identifiable preclinical stage and indicator of risk for cognitive decline in Alzheimer’s Disease and related dementias (ADRD). Identification of individuals in this stage though is difficult, as they present with objectively normal cognitive evaluation scores, relying instead upon self-report of concern about decline in cognitive abilities. The use of non-invasive in-vivo imaging methods like BOLD functional imaging and diffusion tensor have allowed for complex mapping of both the functional and structural network features unique to this condition. This study furthers this network biomarker map of SCD by investigating the …

Characterization Of Pathological Tau Mutants, Charles J. Mcdonald

Dissertations, Theses, and Capstone Projects

Tau is a protein expressed exclusively in glia and neurons in the central nervous system and implicated in several neurogenerative diseases called “tauopathies”. Among all the tauopathies, one third is characterized by the presence of genetic mutations leading to the synthesis of tau proteins with single amino acid substitutions at specific locations and affecting protein function. While most of the initial studies have emphasize the functional role of tau as modulator of the axonal cytoskeleton, it has recently been well accepted that tau is also an intrinsically disordered protein that tends to form membraneless organelles called coacervates, due to a …

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 …

Rhythms In Barriers And Fluids: Circadian Clock Regulation In The Aging Neurovascular Unit, Lea Skapetze, Sharon Owino, Eng H. Lo, Ken Arai, Martha Merrow, Mary Harrington

Neuroscience: Faculty Publications

The neurovascular unit is where two very distinct physiological systems meet: The central nervous system (CNS) and the blood. The permeability of the barriers separating these systems is regulated by time, including both the 24 h circadian clock and the longer processes of aging. An endogenous circadian rhythm regulates the transport of molecules across the blood-brain barrier and the circulation of the cerebrospinal fluid and the glymphatic system. These fluid dynamics change with time of day, and with age, and especially in the context of neurodegeneration. Factors may differ depending on brain region, as can be highlighted by consideration of …

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 …

Microtubule Polarity Flaws As A Treatable Driver Of Neurodegeneration, Bridie D. Eckel, Roy Cruz Jr., Erin M. Craig, Peter W. Baas

All Faculty Scholarship for the College of the Sciences

Microtubule disruption is a common downstream mechanism leading to axonal degeneration in a number of neurological diseases. To date, most studies on this topic have focused on the loss of microtubule mass from the axon, as well as changes in the stability properties of the microtubules and/or their tubulin composition. Here we posit corruption of the normal pattern of microtubule polarity orientation as an underappreciated and yet treatable contributor to axonal degeneration. We include computational modeling to fortify the rigor of our considerations. Our simulations demonstrate that even a small deviation from the usual polarity pattern of axonal microtubules is …

Neuronal Primary Cilia In Postnatal Brains & Alzheimer’S Disease Mice Eeg Patterns Under Fear Conditioning, Sierra Rose Mae Walsh

Honors Theses and Capstones

Alzheimer’s Disease (AD) is a neurodegenerative condition caused by the abnormal accumulation of amyloid β plaque. While small amounts of amyloid β plaque is to be expected with increased age, AD presents amyloid precursor protein (APP), a gene promoting inappropriate plaque formation, causing early neuronal death and tissue depreciation. APP23 transgenic mouse models contain the human mutation in the neocortical and hippocampal positions, areas revealing of plaque accumulation and memory loss. Within the hippocampal cortices, the primary cilia, which regulate higher cognition and neurodevelopment can be studied along with burst suppressions, or moments of high focal activity, to target potential …

Repeated Occupational-Level Exposure To The Pesticide Malathion Leads To Neuronal Atrophy In The Dorsal Root Ganglion, Arian K. Mcneil

Browse all Theses and Dissertations

Environmental exposure to organophosphate (OP) pesticides, such as malathion, is a risk factor for neuropathy and neurodegeneration. Toxic levels of OPs irreversibly inhibit acetylcholinesterase (AchE) activity, leading to acute paralysis and even death as the neurotransmitter acetylcholine accumulates at cholinergic synapses. In addition, there is compelling evidence that repeated low-level “occupational-like” exposure to OPs is associated with somatosensory defects but the cellular mechanisms for this effect are unclear. We show sensory neuron cell size in the dorsal root ganglia is significantly reduced in rats exposed to occupational level malathion. However, co-administration of a reversible AchE inhibitor, galantamine, prevented this effect.

Unraveling The Consequence Of Adult Onset Sulfatide Depletion: Its Implications In Myelin And Axonal Heath In The Context Of Neurodegenerative Disease, Elizabeth Dustin

Theses and Dissertations

Multiple Sclerosis is an immune mediated disease of the CNS. MS is diagnosed through detection of demyelinated regions. However, recent studies demonstrate that Normal Appearing White Matter (NAWM) contains substantial pathology. One such pathology observed in the NAWM is the reduction of sulfatide. The proper stoichiometry of lipids in myelin acts to maintain rapid conduction velocity, provide trophic support to the neuron, and protect the axon from degeneration. We previously characterized a mouse lacking sulfatide’s synthesizing enzyme, CST through constitutive gene disruption and demonstrate that sulfide is required for proper stability of the myelin sheath. However, since MS is typically …

Mechanism Of Tau Propagation: Putative Therapeutic Approaches, Viktoriya Morozova

Dissertations, Theses, and Capstone Projects

One of the characteristics of Alzheimer’s disease and associated tauopathies is the accumulation and aggregation of hyperphosphorylated tau protein. The biological activity of tau is to bind to tubulin and promote its assembly into microtubules with subsequent stabilization of the latter. When tau gets hyperphosphorylated it cannot bind to tubulin and carry on its function, instead, it binds to normal tau and sequesters it from microtubules leading to disruption of microtubular assembly and ultimately to the death of neurons. Our lab had previously shown that tau phosphorylation sites 199, 212, 231, and 262, combined with the FTDP-17 mutation R406W (Pathological …

Transcriptional Mechanisms Of Neuroprotection In Excitotoxicity Driven Neurodegeneration In C. Elegans, Zelda Z. Mendelowitz

Dissertations, Theses, and Capstone Projects

Excitotoxicity is notorious for triggering neuronal cell death in both developmental and adult-onset neurodegenerative diseases. In excitotoxicity, excessive concentrations of Glutamate in the synapse overstimulate Glutamate Receptors (GluRs) on postsynaptic neurons. While GluR mediated degenerative mechanisms remain obscure, GluR activation was surprisingly found to also have a neuroprotective effect through activation of specific transcriptional programs. To identify evolutionarily conserved transcriptional programs in neuroprotection we use a C. elegans model of excitotoxic necrosis (glt-3;nuIs5). We have identified that non-canonical activation of the transcription factor CRH-1/CREB mediates neuroprotection in our excitotoxicity model. We found the Histone Acetyl Transferase, MYS-1/KAT6, and the neuronal …

Importin-Mediated Pathological Tau Nuclear Translocation Causes Disruption Of The Nuclear Lamina, Tdp-43 Mislocalization And Cell Death, Robert F. Candia, Leah S. Cohen, Viktoriya Morozova, Christopher Corbo, Alejandra D. Alonso

Publications and Research

Tau is a cytosolic protein that has also been observed in the nucleus, where it has multiple proposed functions that are regulated by phosphorylation. However, the mechanism underlying the nuclear import of tau is unclear, as is the contribution of nuclear tau to the pathology of tauopathies. We have previously generated a pathological form of tau, PH-tau (pseudophosphorylation mutants S199E, T212E, T231E, and S262E) that mimics AD pathological behavior in cells, Drosophila, and a mouse model. Here, we demonstrated that PH-tau translocates into the nucleus of transiently transfected HEK-293 cells, but wildtype tau does not. We identified a putative …