Expression of Macrophage Inflammatory Protein 1-α is Elevated in Alzheimer's Vessels and is Regulated by Oxidative Stress

Abstract

Inflammatory mediators are highly expressed in the Alzheimer's disease (AD) brain. We have shown that in AD the cerebral microcirculation is a rich source of cytokines and chemokines including interleukins (IL) 1β, IL-6, IL-8, tumor necrosis factor-α, and monocyte chemoattractant protein-1. However, the factors that regulate expression of these inflammatory proteins have not been defined. The objective of this study is to compare expression of macrophage inflammatory protein 1-α (MIP-1α) in brain microvessels isolated from AD patients to vessels from age-matched controls and further to determine whether expression of MIP-1α in brain endothelial cells is altered by oxidative stress. The data show that brain AD-derived microvessels express high levels of MIP-1α mRNA and release high levels of MIP-1α protein compared to brain microvessels isolated from controls. Treatment of brain endothelial cell cultures with menadione, a superoxide releasing compound, hydrogen peroxide, lipopolysacharride, or oxidatively modified low density lipoproteins (LDL) (Ox-LDL, HNE-LDL) results in a dose- dependent increase in MIP-1α mRNA levels and MIP-1α release into the media. These results suggest that oxidative and lipid insults to the brain microvasculature are likely to contribute to the inflammatory milieu of the AD brain.