ORCID
https://orcid.org/0000-0002-2545-0230
Date of Award
2022
Document Type
Dissertation
Degree Name
Psychology (Psy.D.)
Department
Pharmaceutical Sciences
First Advisor
Sandra Reznik
Second Advisor
John Wurpel
Third Advisor
Zhe-Sheng Chen
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder with no cure, accounting for 60-80% of cases of dementia. While the two pathologic hallmarks of AD, senile plaques from extracellular deposition of amyloid β-protein (Aβ) and tau-based neurofibrillary tangles (NFT), have been known for decades, the pathogenesis of AD remains unclear. In recent years, anti-neuroinflammatory treatment has entered the spotlight in AD research. In previous studies, we have shown that N,N-dimethylacetamide (DMA), a common drug excipient, is a potent anti-inflammatory agent. In the current work, we investigate the effect of DMA on neuroinflammation and its mechanism of action in in-vitro and ex-vivo models. We show that DMA significantly suppresses the production of inflammatory mediators, such as reactive oxygen species (ROS), nitric oxide (NO), various cytokines and chemokines and Aβ in both mouse microglia SIM-A9 cells and human microglia HMC3 cells stimulated by lipopolysaccharide (LPS). DMA also significantly inhibits the mRNA and protein levels of amyloid precursor protein (APP), the precursor molecule of Aβ. We also demonstrate that DMA inhibits Aβ-induced inflammation by attenuating the production of pro-inflammatory cytokines and chemokines in activated microglia. Moreover, DMA significantly downregulates the expression of pro-inflammatory cytokines and chemokines in mouse hippocampal slices. The mechanism behind DMA’s attenuation of neuroinflammation is through inhibition of degradation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor α (IκBα) and translocation of nuclear factor kappa-B p65 (NF-κB p65) to inhibit activation of the NF-κB signaling pathway. DMA has no effect on downstream proteins of the mitogen-activated protein kinase (MAPK) pathway. Taken together, our findings suggest that DMA targets neuroinflammation in AD via inhibition of the NF-κB pathway.
Recommended Citation
Wei, Zenghui, "N, N-DIMETHYLACETAMIDE TARGETS NEUROINFLAMMATION IN ALZHEIMER’S DISEASE IN IN VITRO AND EX VIVO MODELS" (2022). Theses and Dissertations. 724.
https://scholar.stjohns.edu/theses_dissertations/724