ORCID

https://orcid.org/0009-0001-8740-7721

Date of Award

2026

Document Type

Dissertation

Degree Name

Pharmaceutical Sciences (Ph.D.)

Department

Pharmaceutical Sciences

First Advisor

Sandra E Reznik

Second Advisor

Jeanette Perron

Third Advisor

Marta Concheiro-Guisan

Abstract

Neurological function is closely linked to both longevity and quality of life. While some degree of neurodegeneration occurs naturally with aging, pathological neurodegeneration leads to devastating functional decline. The mechanisms underlying these processes remain incompletely understood; however, neuroinflammation is recognized as a key driver of neuronal dysfunction and death. Emerging evidence indicates that neuroinflammatory cascades can precede and potentiate hallmark features of neurodegenerative diseases, including synaptic loss and cognitive decline observed in Alzheimer’s disease (AD). Activation of the NF-κB signaling pathway contributes to amyloid beta (Aβ) peptide production, further amplifying a cycle of inflammation and neuronal injury. Preclinical work from the Reznik laboratory has demonstrated that the FDA-approved excipient N,N-dimethylacetamide (DMA) disrupts NF-κB signaling, attenuates Aβ-induced inflammation, and dismantles the positive feedback loop between NF-κB activation and Aβ synthesis in vitro and ex vivo. Building on these findings, the present study investigates the efficacy of DMA in vivo using a lipopolysaccharide (LPS)-induced mouse model of neuroinflammation. LPS, a bacterial endotoxin consistently detected in the brains of patients with neurodegenerative disease, is a well-established tool for modeling chronic neuroinflammatory states. This dissertation evaluates the therapeutic potential of DMA in C57BL/6 mice by examining behavioral outcomes, neuroinflammatory markers, and transcriptomic alterations. Key endpoints include cognitive performance (Radial Arm Maze, Novel Object Recognition), cytokine expression (IL-1β, IL-6, TNF-α), and microglial activation. By employing a wild-type model, this work aims to reflect the sporadic, environmentally linked nature of human neurodegeneration rather than transgenic predisposition. Collectively, these studies seek to determine whether DMA can attenuate neuroinflammation and protect against inflammation-associated neurodegeneration. Findings from this work may advance DMA as a novel, inexpensive, and translationally viable therapeutic strategy for mitigating the progression of neurodegenerative disease.

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