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Thesis Seminars

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Investigating Glatiramer Acetate’s Mechanism of Action in the 5xFAD Alzheimer’s Disease Model

Berke Karaahmet
Advisor: Kerry O’Banion, Ph.D.
- Ph,D, Thesis Proposal

Alzheimer’s disease (AD) is the most common form of dementia and its prevalence is expected to rise. The most striking molecular pathology in AD is the extracellular protein aggregates, termed amyloid plaques. It is established that peripheral immunomodulatory interventions can alter this histopathological hallmark and are associated with improved outcomes. Our lab has previously observed that the relapsing remitting Multiple Sclerosis (MS) drug Glatiramer Acetate (GA, Copaxone®) can improve amyloid and tau pathology, and ameliorate cognitive impairments in the 3xTg AD mouse model. Although our group and others have shown that GA treatment decreases amyloid pathology across a variety of models, the exact mechanism of this elusive drug, even in its principle applications, remains unclear. Similar to the findings from literature concerning animal models of MS, we hypothesize that GA modulates both CD4+ T cell and monocyte function towards a phenotype more conducive to tissue repair and homeostasis, and both these cell types have potential to mediate protection from amyloid pathology.
In Aim 1, we will investigate the necessity and sufficiency of CD4+ T cells in GA’s mechanism of action through antibody-mediated depletion studies under GA treatment and adoptive transfers of CD4+ T cells from GA vaccinated donors into 5xFAD hosts which develop amyloid pathology much faster than other common AD models. In addition, we will test whether a Th2 transcriptional profile and migration into the brain parenchyma, the two components of “bystander suppression” hypothesis, are required for GA’s mechanism in AD. In Aim 2, we will investigate whether monocytes are sufficient and necessary in GA’s mechanism of action by adoptive transfer of monocytes isolated from GA treated mice and liposome mediated depletion studies. Furthermore, we will confirm that GA modulates the expression of several key transcripts in monocyte phenotype and also attempt to understand the crosstalk between monocytes and CD4+ T cells in development of a response to GA by adoptively transferring monocytes from GA treated Rag2-/- donors. Altogether, this project will identify key, easily accessible peripheral immune players in GA’s mechanism. Greater understanding in this domain will help repurpose a drug with an excellent safety profile to a new context and give insights into the impact of peripheral immune cell types in AD.

 Dec 11, 2019 @ 10:45 a.m.

 Medical Center | 3-7619 Upper Auditorium

Human herpesvirus 6A latency gene U94A impairs motility and maturation in glial cells and neurons: Implications for neurodegenerative disease

Jessie Hogestyn
Advisor: Dr. Margot Mayer-Pröschel
- Ph.D. Thesis Defense

Many neurodegenerative diseases have a multifactorial etiology and variable course of progression that cannot be explained by current models. Neurotropic viruses have long been suggested to play a role in these diseases, although their exact contributions remain unclear. Human herpesvirus 6A (HHV-6A) is one of the most common viruses detected in the adult brain, and has been clinically associated with multiple sclerosis (MS), and, more recently, Alzheimer’s disease (AD). HHV-6A is a ubiquitous viral pathogen capable of infecting glia and neurons. Primary infection in childhood is followed by the induction of latency, characterized by expression of the U94A viral transcript in the absence of viral replication. Our work is the first to examine the effects of this common viral gene on cells of the central nervous system. We found that U94A expression inhibits the migration and maturation of human oligodendrocyte precursor cells (OPCs) without affecting their viability, a phenotype that may contribute to the failure of remyelination seen in many patients with MS. Large-scale transcriptomics and proteomics analyses indicate that U94A expression in OPCs alters the expression of genes involved in cytoskeletal regulation and in cellular interactions with the extracellular matrix, while preliminary biochemical analyses suggest that U94A may exert its functions by interacting with nucleosomes and with myosin motors. As HHV-6A seems to be significantly associated with early AD pathology, we extended our initial analysis of U94A in OPCs to cytoskeletal abnormalities in neurons. We found that U94A expression inhibits morphological maturation in human cortical neurons. Given that morphological abnormalities are known to precede synapse loss and cognitive impairment in AD patients, we hypothesize that U94A expression in neurons renders them more susceptible to dysfunction and degeneration. Our work suggests that the persistent presence of HHV-6A-associated proteins establishes a state of vulnerability that can contribute to disease progression in MS and AD. We propose this virus as a unique human factor to consider in the translation of therapies from animal models to human patients.

 Dec 09, 2019 @ 1:00 p.m.

 Medical Center | G-9425 Class of '62 Auditorium

Functional Brain Network Structure in Focal Embouchure Dystonia and Related Disorders

Aimee Morris - Neuroscience PhD Candidate

 Jul 01, 2019 @ 2:00 p.m.

 Medical Center | Lower Adolph Auditorium 1-7619

Host: Dr. Jonathan Mink

Noradrenergic modulation of microglial dynamics and synaptic plasticity

Rianne Stowell - Neuroscience PhD Candidate

 Jun 28, 2019 @ 1:00 p.m.

 Medical Center | Auditorium K-307

Host: Dr. Ania Majewska

Ameliorating Alzheimer’s Disease tau pathology through immunomodulation: A novel role for interleukin 4 and glatiramer acetate

Dawling Dionisio-Santos - Neurobiology and Anatomy PhD Candidate

 Jun 26, 2019 @ 1:00 p.m.

 Medical Center | Upper Auditorium 3-7619

Host: Dr. Kerry OBanion

NSC Thesis Proposal: Investigating changes in population coding in the APP/PS1 mouse model of Alzheimer’s disease

Uday Chockanathan - Ph.D. Candidate - Advisor: Krishnan Padmanabhan

 May 01, 2019 @ 11:00 a.m.

 Medical Center | 2-6424 Whipple Auditorium

NSC Thesis Proposal - The role of PI3Kg signaling in microglial dynamics and experience dependent synaptic plasticity

Brendan Whitelaw - Ph.D. Candidate
Advisor: Ania Majewska

 Feb 19, 2019 @ 10:00 a.m.

 Medical Center | K-207 (2-6408)