Defense Date

2022

Document Type

Thesis

Degree Name

Master of Science

Department

Anatomy & Neurobiology

First Advisor

Dong Sun, MD PhD

Second Advisor

Andrew Ottens, PhD

Third Advisor

Xiang-Yang Wang, PhD

Abstract

Alzheimer’s Disease (AD) is a progressive neurogenerative disease that affects millions globally. At this time there are no effective treatment options as the primary cause for AD is not fully understood. In addition to old age, genetic predisposition, and certain health conditions, traumatic brain injury (TBI) has been identified as a risk factor for AD. While the pathway that links TBI to AD is still largely unknown, the neuroinflammatory response to both conditions has been connected to the NLRP3 inflammasome. Due to its role in the innate immune system and proinflammatory cytokine mediation, the NLRP3 inflammasome could be a potential therapeutic target for reducing damage caused by post-TBI inflammation.

In the current study, we examined how reduction of NLRP3 alters post-TBI neuroinflammation in the context of predisposition of AD. Using 3xTg AD mice, a widely used transgenic AD mice model, and 3xTg AD/NLRP3-/- mice, a strain created in our lab with specific deletion of NLRP3 gene in the 3xTg AD mice, as well as the matched wild type control strain, we measured the TBI-induced neuroinflammatory response related to NLRP3 inflammation following TBI at the acute stage (2 days post injury). The central fluid percussion injury (cFPI) model of TBI was used and protein analysis was done using Western blotting and ELISA methods.

Results suggested that TBI causes a trend of enhanced expression of NRLP3, active caspase-1, IL-1b, and GFAP, however, results only reached significance for GFAP. HMGB1 expression was unaltered by TBI. The 3xTg animals had higher expression of NLRP3 and active caspase-1 compared to 3xTg/KO. This study suggests that a moderate cFPI, the TBI model used for this study, does not cause increased NLRP3 inflammasome activation or microglial activation but does suggest TBI causes enhanced astrogliosis. It is inconclusive whether predisposition to AD leads to enhanced neuroinflammatory and microglial cell response. However, as evidenced by higher caspase-1 expression in 3xTg mice compared to 3xTg/NLRP3-/- mice, there is some data that supports predisposition to AD causes increased formation of the NLRP3 inflammasome and that reduction of NLRP3 in the context of predisposition of AD can mediate this response. Understanding the link between TBI and AD is crucial in developing post-TBI treatments. Future studies should analyze the inflammatory/immune response at the chronic stage post-TBI as well as how different TBI models and intensities would affect inflammatory/immune response.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-11-2022

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