Date of Award
2024
Document Type
Dissertation
Degree Name
Philosophy (Ph.D)
Department
Pharmaceutical Sciences
First Advisor
Francis A.X Schanne
Second Advisor
Jeanette C Perron
Third Advisor
John Wurpel
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease associated with memory decline and cognitive impairment. It is a growing global health and socioeconomic concern, affecting more than 50 million people worldwide. Current therapeutics focus solely on symptomatic management instead of preventative or curative strategies. This is mainly a result of the complexity of the pathophysiological mechanism and the poor understanding of the disease progression. Recently, studies have focused on bridging knowledge gaps giving rise to substantial evidence on the vital role of neuroinflammation in the progression of AD. Neuroinflammation has been shown to be a precursor to apparent amyloid plaque accumulation and subsequent synaptic loss and cognitive decline. The increased activity of microglia and their release of complement proteins has been shown to be the key initiators to neuroinflammation in AD. In this study, the effect of a novel small molecule complement C1r inhibitor, called T-ALZ01, to inhibit the inflammatory processes that cause neuroinflammation in vivo and in vitro was determined. In the in vitro studies, T-ALZ01 demonstrated a significant reduction (p ≤ 0.05) in the levels of the inflammatory cytokines, IL-6 and TNF-α. Regarding in vivo studies, an LPS-induced inflammatory Sprague Dawley rat model, whereby animals were injected intraperitoneally with 0.5 mg/kg LPS O55:B5, was used to analyze the effect of T-ALZ01 in inhibiting inflammatory process associated with AD. Moreover, the inability of T-ALZ01 to cross the blood-brain barrier resulted in considering the use of exosomes (nanosized, endogenous extracellular vesicles) as a drug delivery vehicle. Intranasally administered exosomes loaded with T-ALZ01 demonstrated significant reduction (p ≤ 0.05) in degenerating neurons and the activation of resident microglia and astrocytes, as well as inflammatory markers in vivo. Thus, T-ALZ01 showed efficacy in reducing the severity of neuroinflammation in AD. This study demonstrates a significant use of small molecule complement inhibitors via exosome drug delivery as a possible therapeutic in AD.
Recommended Citation
Richards, Terjahna, "THERAPEUTIC INTERVENTION OF NEUROINFLAMMATION IN ALZHEIMER DISEASE BY INHIBITION OF CLASSICAL COMPLEMENT PATHWAY USING ANTI-C1R LOADED EXOSOMES" (2024). Theses and Dissertations. 718.
https://scholar.stjohns.edu/theses_dissertations/718