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Design of amphiphilic macromolecule and antioxidant based nanotherapeutics for microglia-mediated neuroinflammation in synucleinopathy
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Zhao, Nanxia. Design of amphiphilic macromolecule and antioxidant based nanotherapeutics for microglia-mediated neuroinflammation in synucleinopathy. Retrieved from https://doi.org/doi:10.7282/t3-geg5-dy16

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TitleDesign of amphiphilic macromolecule and antioxidant based nanotherapeutics for microglia-mediated neuroinflammation in synucleinopathy
NameZhao, Nanxia (author); Moghe, Prabhas (chair); Roth, Charles M. (member); Chundawat, Shishir P.S. (member); Uhrich, Kathryn E. (member); Kholodovych, Vladyslav (member); Rutgers University; School of Graduate Studies
Date Created2022
Other Date2022-05 (degree)
SubjectChemical engineering, Biomedical engineering, Microglia, Nanotechnology, Neuroinflammation, Scavenger receptor, Synuclein
Extent215 pages : illustrations
DescriptionAs one of the main types of synucleinopathies, Parkinson’s disease (PD) is a progressive neurodegenerative disorder, characterized by the accumulation and aggregation of alpha synuclein (aSYN) and neuroinflammation, with deficits in dopaminergic (DA) neurons. Current pharmacological treatment options for PD provide temporary motor symptom relief via stimulating the dopamine production from remaining DA neurons, but fail to address the continuing loss of DA neurons as PD progresses, and thus lack long-term efficacy. As the predominant resident immune cells of the central nervous system, microglia, are emerging as a promising cellular target for neurodegeneration considering their prominent role in the clearance and degradation of alpha synuclein and neuroinflammation. The critical need for disease modifying therapeutics and the lack of microglia-focused pharmacological interventions for PD inspired the research focus of this dissertation, which is concerned with the mechanistic basis for the design of innovative nanotherapeutics addressing microglia-related pathology in PD. Specifically, we investigated two nanotherapeutic approaches to address two key pathophysiologic phenomena that concertedly exacerbate PD: (1) antioxidant nanoparticles (NPs) to inhibit intracellular α-synuclein oligomerization with a view to lower microglial oxidative stress, and (2) amphiphilic molecule (AM)-based nanoparticles to attenuate aSYN-binding induced-microglial activation and neuroinflammation.
To address aSYN protein aggregation, dual antioxidant component NPs containing a ferulic acid-derived molecule shell and tannic acid core were fabricated. We found that these antioxidant NPs can inhibit aSYN fibrillization, lower intracellular aSYN oligomer formation in microglia and the release of neurotoxic free radicals from microglia. To address aSYN-induced neuroinflammation, in silico molecular docking approaches were used to explore the design of new AMs with enhanced binding affinity to CD36 receptor and stronger inhibitory activity towards CD36-aSYN interactions, one of the earliest events initiating the neuroinflammatory cascade. Our in-silico findings led to the design and synthesis of four new compositionally variant tartaric acid-based AMs with different alkyl side chain length. Biological characterization of these AMs in NP formulations revealed that these AM NPs can block aSYN-CD36 interactions, inhibit proinflammatory molecules production from aSYN-challenged microglia, modulate microglia activation, and diminish microglial neurotoxicity.
Overall, the cumulative findings in this dissertation provide new insights for future design of nanotherapeutics to ameliorate some of the key factors that lead to the progression of PD pathology.
NotePh.D.
NoteIncludes bibliographical references
Genretheses
Persistent URLhttps://doi.org/doi:10.7282/t3-geg5-dy16
LanguageEnglish
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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