Time-dependent determination of inflammatory mediators in a 5xFADmouse model of Alzheimer's disease Pubblico

Abstract

The inflammatory process has been shown to play a significant role in the pathogenesis of AD (Rubio-Perez and Morillas-Ruiz, 2012). Inflammatory mediators related to AD include glial cells such as astrocytes and microglia in addition to cytokines and chemokines. In neurodegenerative diseases such as Alzheimer's, inflammatory changes can facilitate neuronal dysfunction and cell injury and may be a potential mechanism that exacerbates these effects over time (Zhang and Jiang, 2015). The goal of the current experiment is to analyze inflammatory gene expression in a time-dependent manner using the 5x Familial Alzheimer's disease (FAD) mouse model. A key question of interest is whether or not COX-2 differs between 5xFAD and WT mice. COX-2 has been shown to increase in Braak stages 0 - II, yet decrease in Braak stages V and VI. Therefore, this study aims to determine the time of COX-2 induction, and whether this is concurrent with plaque development during the early stages of AD. In this experiment, quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze the mRNA fold changes of male and female WT and 5xFAD mice at 3 different time-points: 2-, 3-, and 4-months of age. The 9 genes that were examined were: COX-2, TNF-alpha, IL-1beta, CCL2, CXCL10, IL-6, GFAP, IBA1, and EP2. It was found that in 5xFAD males, COX-2 was continuously increasing from 2- to 4-months and was the only gene that was induced at 4-months. In 5xFAD females, both CXCL10 and GFAP were increasing from 2- to 4-months and were significantly upregulated at both 3- and 4-months. Essentially, this study can be used to better understand changes in inflammatory gene expression during the initial stages of AD where beta-amyloid plaque pathology begins and continues to escalate over time.

Table of Contents

Introduction. 2

Materials and Methods. 13

Results. 19

Figures and Tables

Figure 1a. 19

Figure 1b. 19

Figure 2. 22

Figure 3. 23

Figure 4. 23

Figure 5. 24

Discussion. 25

Future Directions. 29

Conclusion. 31

Limitations. 32

References. 33

Supplementary Material

Figure 6. 40

Figure 7. 41

Figure 8. 41

Table 1a. 42

Table 1b. 42

Table 2a. 43

Table 2b. 43

Table 3a. 44

Table 3b. 44

Table 4a. 45

Table 4b. 45

Table 5. 46

Table 6. 46

Table 7. 46

About this Honors Thesis

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• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Emory College
Department	Neuroscience and Behavioral Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Neuroscience Health Sciences, Pharmacology
Parola chiave	gliosis inflammation cyclooxygenase-2 pro-inflammatory cytokines EP2 chemokines Alzheimer's disease prostaglandins
Committee Chair / Thesis Advisor	Ganesh, Thota, Emory University
Committee Members	Konner, Melvin J, Emory University Dingledine, Raymond J, Emory University Sober, Samuel J, Emory University

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