Relationship between inflammatory mediators, Aβ levels and ApoE genotype in Alzheimer disease

Abstract

Activation of inflammatory processes is observed within the brain as well as periphery of subjects with Alzheimer's disease (AD). Whether or not inflammation represents a possible cause of AD or occurs as a consequence of the disease process, or, alternatively, whether the inflammatory response might be beneficial to slow the disease progression remains to be elucidated. The cytokine IL-18 shares with IL-1 the same pro-inflammatory features. Consequent to these similarities, IL-18 and its endogenous inhibitor, IL-18BP, were investigated in the plasma of AD patients versus healthy controls (HC). An imbalance of IL-18 and IL-18BP was observed in AD, with an elevated IL-18/IL-18BP ratio that might be involved in disease pathogenesis. As part of the inflammatory response, altered levels of RANTES, MCP-1 and ICAM- 1, molecules involved in cell recruitment to inflammatory sites, were observed in AD. Hence, correlations between IL-18 and other inflammatory plasma markers were analyzed. A negative correlation was observed between IL-18 and IL-18BP in both AD and HC groups. A positive correlation was observed between IL-18 and ICAM-1 in AD patients, whereas a negative correlation was evident in the HC group. IL-18 positively correlated with Aβ in both groups, and no significant correlations were observed between IL-18, RANTES and MCP-1. An important piece of evidence supporting a pathophysiologic role for inflammation in AD is the number of inflammatory mediators that have been found to be differentially regulated in AD patients, and specific ones may provide utility as part of a biomarker panel to not only aid early AD diagnosis, but follow its progression.

Figure 1

Correlation coefficient between IL-18 concentration and inflammatory molecules analyzed in plasma of Alzheimer Disease (AD) patients and healthy controls (HC) subjects.

Figure 2

Expression of IL-18 and IL-18BP mRNA in patients with Alzheimer Disease (AD) and in healthy controls (HC).

Figure 3

Box-whiskers graphs of IL-18 and IL-18BP levels in AD patients, stratified in ApoE-ε4, ApoE-ε3 and ApoE-εs2, and HC subject. Box-whiskers plots show the 25th and 75th percentile range (box) and median values (transverse lines within the box). Statistically significant differences were found between four groups (p-value of Kruskal-Wallis post hoc test).

Figure 4

mRNA levels of IL-18 and IL-18BP in AD patients with different ApoE-ε genotypes. PBMC mRNA levels were analyzed by semiquantitative RT-PCR using primers for hIL-18, hIL-18BP and β-actin.

Figure 5

Fold-increase of Aβ-mediated mRNA expression of IL-18 and IL-18BP in THP-1 monocytes and PBMCs. Data are representative of three separate experiments. The intensities of bands for IL-18 and IL-18BP are normalized to the 18S signals. Quantification of three separate experiments was performed. The data are expressed as the fold increase relative to mRNA expression of each gene in LPS-stimulated THP-1 and PBMC cells. Data are representative of pooled experiments.

Figure 6

Secretion of IL-18 and IL-18BP in response to LPS+Aβ. PBMC and THP-1 cells were cultured in RPMI containing Aβ (10 μg/ml) and were incubated for 18 hr in the presence or absence of LPS (10 μg/ml). The data represent the fold-increase over the LPS-induced IL-18 and IL-18BP production.