Graduation Date

Spring 5-7-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Dr. Howard E Gendelman

Second Advisor

Dr. R. Lee Mosley

MeSH Headings

Parkinson's Disease, Alzheimer's disease

Abstract

Modulating the immune system via. transformation of CD4+ T cell effector to regulatory (Teff to Treg) or promoting microglial clearance of abnormal disease proteins are attractive therapeutic strategies to restore immunological balance in neurodegenerative diseases like Parkinson’s disease (PD) and Alzheimer’s disease (AD). In the past decade, we defined a safe and effective pathway for Treg induction through the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF was developed in PD animal models and early phase I human studies demonstrating proof-of-concept efficacy for ameliorating disease signs and symptoms. Despite the recorded efficacy, the medicine’s short half-life, limited bioavailability, and injection site reactions proved to be, in measure, limitations for broader use. To address these limitations, a long-acting lipid nanoparticle (LNP) formulation of mouse and rat GM-CSF mRNA (coined as Msa-mm-GMCSF and Rsa-GM-CSF, respectively) were developed for their immunomodulatory and neuroprotective activities in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse and the human wild type alpha-synuclein overexpression rat PD models. A single dose of both mouse and rat formulation generated plasma cytokine levels up to 4 days with sustained Treg numbers and improved function, reduced numbers of reactive microglia, and protected the nigrostriatum beyond what was recorded for daily recombinant GM-CSF administration in both disease models. Mechanistic

evaluation of neuropathological-focused transcriptomic profiles of the affected nigral region showed increased upregulation of three key neuroprotective pathways, CREB and synaptogenesis signalling in neurons and neurovascular coupling.

Further, we looked at the broad free radical scavenging and antioxidant activities of Cerium oxide nanoparticle’s (CeO2NPs) at reducing neuroinflammation and enhancing uptake of misfolded amyloid beta (Aβ) proteins by microglia. CeO2NPs have shown protective effects in AD experimental models. However, CeO2NPs effects on the brain resident microglia cells under the setting of AD have not been fully understood yet. Here, we synthesized and characterized unique europium conjugated CeO2NPs (EuCeO2NPs) and studied their effects on BV2 microglia cells in the presence of Aβ1-42. Treatment of EuCeO2NPs improved Aβ phagocytic activity of BV2 cells and significantly upregulated the scavenger receptor CD36 expression on BV2 microglia cells and Aβ uptake and degradation. EuCeO2NPs also abrogated inflammatory responses provoked by lipopolysaccharide (LPS) in BV2 cells suggesting their ability to modify the microglial phenotype and restore their homeostatic functions.

These data, taken together, demonstrate that immunomodulation and restoring immune homeostasis are important therapeutic targets for treatment of neurodegenerative diseases.

Available for download on Thursday, January 26, 2023

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