Effect of soluble TNF signaling on blood-brain barrier permeability and neuroinflammation in a 5xFAD mouse model of Alzheimer’s disease fed a high-fat high-fructose diet Restricted; Files Only

Sniffen, Lindsey (Spring 2018)

Permanent URL: https://etd.library.emory.edu/concern/etds/qz20ss555?locale=en
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Abstract

In the United States, there are over 5 million people living with Alzheimer’s Disease (AD), and the prevalence is expected to increase as the population ages (Alzheimer’s Association, 2016). One risk factor for AD is metabolic disorders such as type 2 diabetes which increases risk for AD by 65% (Xu, 2011). Consuming a high-fat and high-sugar diet causes weight gain and is a risk factor for metabolic disorders. Both metabolic disorders such as type 2 diabetes and AD have an increase in chronic low-level inflammation in the brain and body that can activate the immune system (de Sousa Rodrigues, 2016). A proposed mechanism for this inflammation is through soluble tumor necrosis factor (solTNF). Increased inflammation can damage the blood-brain barrier (BBB) and increase its permeability. The BBB consists of membrane proteins such as claudin 2 (CLDN2) and zona occludins-1 (ZO-1) on the surface of endothelial cells to form tight junctions (Stamatovic, 2008). Chemokine (C-C motif) ligand 2 (CCL2) attracts CCR2 expressing macrophages to the site of inflammation (Khoury, 2007). Cluster of differentiation 45 (CD45) is highly expressed on monocytes and is increased with increases of neuroinflammation (Jeong, 2013). IL-6 is a proinflammatory cytokine that is secreted by T-cells and brain immune cells. Using qPCR, we observed hippocampal mRNA expression of TNF, CCL2, ZO-1, CLDN2, CD45, and IL-6. We also looked at hippocampal protein expression of ZO-1. We analyzed 5-point familial Alzheimer’s Disease (5xFAD) and wild-type mice either fed a control diet (CD) or high-fat high-fructose (HFHF) diet. Some mice from each group were also administered Xpro® 1595, which inhibits solTNF signaling (MacPherson, 2017), to observe its effects on inflammatory markers. Our study demonstrates that HFHF diet increases hippocampal inflammation as measured by TNF mRNA in WT mice, XPro reduces TNF mRNA levels in the hippocampus of TG mice, and 5xFAD mice fed a HFHF diet have increased CCL2 mRNA in the hippocampus that is ameliorated by blockade of solTNF signaling with XPro®1595.

Table of Contents

Introduction…………………………………………………………………………1

Methods….…………………………………..……………………………………...6

            Table 1………………………………………………………………………6

            Table 2………………………………………………………………………7

Results……………………………………………………...………………………10

            Figure 1……………………………………………………………………..11

            Figure 2……………………………………………………………………..14

            Figure 3……………………………………………………………………..18

            Figure 4……………………………………………………………………..19

            Figure 5……………………………………………………………………..20

            Figure 6……………………………………………………………………..22

Discussion…………………………………………………………………………..23

References…………………………………………………………………………..28

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