Date of Award

2021-12-01

Degree Name

Doctor of Philosophy

Department

Environmental Science and Engineering

Advisor(s)

Mahesh M. Narayan

Abstract

Neurodegenerative diseases are a common affliction of the Central Nervous System. They are caused by age, genetics, and environmental factors. Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis are well-known among the host of neurodegenerative disorders, with Alzheimer's disease and Parkinson's disease being the leading pathologies across this canvas. It is known that the pathogenesis of neurodegenerative diseases is multifactorial due to the involvement of genetic mutations, radical-induced protein damage, abnormal aggregation of misfolded proteins, and the formation of amyloid deposits. The amyloid proteins in neurodegenerative disease include Tau and Amyloid (Aβ) in Alzheimer's disease and α-Synuclein in Parkinson's disease. The toxic form of these proteins is known to propagate across the vertebrate brain.

Recent findings suggest that one pathological-associated protein can interact with another sequentially unrelated amyloid protein. They tend to influence each other's aggregation and drive neurodegenerative comorbidity. An example of this occurrence is the clinically overlapping symptoms across several neurodegenerative disorders. For example, in Parkinson's disease, α-Synuclein aggregates are copathological with Tau pathology in around 50% of cases. It is believed that their seeding mechanism and cell-to-cell propagation leads to the activation of cellular apoptosis, mitochondrial dysfunction, oxidative stress, accumulation of misfolded protein, and ultimately, the loss of physiological functions. In this study, we evaluate the antioxidant capacity of Brazilin in a cell line model, insulted by a truncated (Aβ 25-35) version of (Aβ 1-42). We tested these phytochemical compounds' radical protect and anti-inhibitory capacity on the amyloidogenic peptide. The result obtained suggest that Brazilin can scavenge free radicals, protect cells from Aβ toxicity, inhibit protein aggregation and maintain cellular homeostasis. In addition, we designed a novel approach to understand the mechanism by which amyloid cross-toxicity propagates. Cross-toxicity is the phenomenon associated with the entry of an amyloid protein into a heterotypic brain region, where the invading amyloid protein is not natively expressed. We probed the molecular and organismal outcomes associated with foreign amyloid infiltration into neurons that do not express it. Post stereotactic introduction of Aβ into the remote regions of the rodent brain (Tegmentum) where Aβ is not constitutively expressed, we observed that Aβ colocalized with α-Synuclein, nigral neuron amyloid that differs in sequence from Aβ. However, our model did not elicit motor abnormalities in tested rats after 3,6,9,12-month post-infusion. Our results help us to understand the role of a neuronal factor in cross-toxicity seen in many neurodegenerative diseases.

Environmental factors such as pesticides, herbicides, metals, among others, predispose the organism to the onset of neurodegenerative diseases in later life, predominantly in urban areas. These substances trigger neurotoxicity and overproduction of free radicals. Free radicals provoke the aggregation of proteins, induce toxicity in dopaminergic neurons, and provoke mitochondrial dysfunction. Next, we evaluated whether Citric Acid Carbon Quantum dots (Cit CQDs) protect against Paraquat in Caenorhabditis elegans. Our result identifies that Cit CQDs possess a potent antioxidant effect against Paraquat-induced neurodegeneration in dopaminergic neurons in C. elegans and SH-SY5Y cell lines. Based on all findings presented in this study, Brazilin and Cit CQDs have a potential therapeutic role in neurodegenerative diseases. Similarly, the novel animal model designed in this study to evaluate cross-toxic outcomes helps us understand the mechanism behind neurodegenerative disease at the molecular level.

Language

en

Provenance

Recieved from ProQuest

File Size

161 p.

File Format

application/pdf

Rights Holder

Gabriela Henriquez

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