Microglia activation and anti-inflammatory regulation in Alzheimer's disease

Abstract

Inflammatory regulators, including endogenous anti-inflammatory systems, can down-regulate inflammation thus providing negative feedback. Chronic inflammation can result from imbalance between levels of inflammatory mediators and regulators during immune responses. As a consequence, there are heightened inflammatory responses and irreversible tissue damage associated with many age-related chronic diseases. Alzheimer's disease (AD) brain is marked by prominent inflammatory features, in which microglial activation is the driving force for the elaboration of an inflammatory cascade. How the regulation of inflammation loses its effectiveness during AD pathogenesis remains largely unclear. In this article, we will first review current knowledge of microglial activation and its association with AD pathology. We then discuss four examples of anti-inflammatory systems that could play a role in regulating microglial activation: CD200/CD200 receptor, vitamin D receptor, peroxisome proliferator-activated receptors, and soluble receptor for advanced glycation end products. Through this, we hope to illustrate the diverse aspects of inflammatory regulatory systems in brain and neurodegenerative diseases such as AD. We also propose the importance of neuronal defense systems, because they are part of the integral inflammatory and anti-inflammatory systems. Augmenting the anti-inflammatory defenses of neurons can be included in the strategy for restoration of balanced immune responses during aging and neurodegenerative diseases.

Fig. 1

Microglial activation in amyloid plaque-enriched areas in Alzheimer's disease brains. Double immunohistochemistry was performed with an antibody against the microglial activation marker MHCII (LN3, MB Biomedical) and an anti-amyloid β peptide antibody (6E10, Covance). The black MHCII immunoreactive profiles are activated microglia, whereas amyloid deposits are shown in brown. a An artificial line was drawn to show less amyloid deposit area to the right and more amyloid deposits to the left; a clear difference between these two sides, demonstrating that the magnitude of microglial activation is greater in the area with more amyloid. b Microglia were assigned numbers 1 to 5 to represent graded intensity of MHCII immunoreactivites. Lower numbers denote lower level of MHCII expression and less activating morphology; whereas number 5 denotes higher level of MHCII expression and highly activated morphology

Fig. 2

Microglial activation with tau pathology in Alzheimer's disease. Double immunohistochemistry was performed with an antibody against the microglial activation marker MHCII (LN3) and an anti-phospho tau antibody (Pierce). The black MHCII immunoreactive profiles are activated microglia, whereas phospho-tau containing neurons and neurites are shown in brown. Tissues were counterstained with neutral red to show the nuclei (in pink). Long arrows in a and c indicated MHCII immunoreactive microglia in association with neurons which are negative for tau-immunoreactivity (in a) or positive for tau-pathology (b). Short arrows in c indicate non-activated microglia expressing low amount of MHCII. MHCII immunoreactive microglia are associated with aberrant phospho-tau immunoreactive neurites (b) and neuritic clusters (d)

Fig. 3

Detection of vitamin D receptor (VDR) mRNA by quantitative polymerase chain reaction. a Microglia isolated from human postmortem brains expressed VDR mRNA and the level was increased significantly by treating with 2 and 5 μM of aggregated Aβ1-42. b The levels of VDR mRNA were detected in mRNA samples of parietal brain tissues of neuropathologically confirmed autopsy cases of 9 ND, 10 MCI, and 13 AD

Fig. 4

The VDR protein expression in human brains. VDR was detected in microglia in neocortical tissues using double immunohistochemistry of a VDR antibody (Epitomics) and the MHCII antibody (LN3). VDR immunoreactivity is in black and the MHCII immunoreactivity is in brown (indicated by arrows). VDR immunoreactivities exhibit in granular profiles (a), and intracellular profile resembling nuclear localization (b)

Fig. 5

Enhancing endogenous anti-inflammatory regulatory systems in Alzheimer's disease (AD). AD is characterized by heightened microglial activation and inflammatory responses which can be caused by increasing oligomeric amyloid β peptide (Aβ), oxidative stress, pro-inflammatory cytokines, and compromised blood brain barrier. These responses driven by activated microglia have been shown to cause neuronal distress and injury (right-pointing red arrow). Emerging evidence indicated that some of the endogenous anti-inflammatory systems might not be functioning properly. Resting microglia contribute to keeping neurons healthy (left-pointing gray arrow). This could be accomplished by proper expression and function of several anti-inflammatory systems, including CD200/CD200R, vitamin D3 (Vit D3)/Vitamin D receptor (VDR), PPAR-γ, and soluble and full-length receptor for advanced glycation end-products (sRAGE and fl-RAGE). Achieving a fine balance of anti-inflammatory regulation of inflammatory responses (up-pointing purple arrow) might be of potential therapeutic value