Microglia in Alzheimer's Disease: Exploring How Genetics and Phenotype Influence Risk

Abstract

Research into the function of microglia has dramatically accelerated during the last few years, largely due to recent genetic findings implicating microglia in virtually every neurodegenerative disorder. In Alzheimer's disease (AD), a majority of risk loci discovered through genome-wide association studies were found in or near genes expressed most highly in microglia leading to the hypothesis that microglia play a much larger role in disease progression than previously thought. From this body of work produced in the last several years, we find that almost every function of microglia has been proposed to influence the progression of AD from altered phagocytosis and synaptic pruning to cytokine secretion and changes in trophic support. By studying key Alzheimer's risk genes such as TREM2, CD33, ABCA7, and MS4A6A, we will be able to distinguish true disease-modulatory pathways from the full range of microglial-related functions. To successfully carry out these experiments, more advanced microglial models are needed. Microglia are quite sensitive to their local environment, suggesting the need to more fully recapitulate an in vivo environment to study this highly plastic cell type. Likely only by combining the above approaches will the field fully elucidate the molecular pathways that regulate microglia and influence neurodegeneration, in turn uncovering potential new targets for future therapeutic development.

Keywords: Alzheimer's disease; genome-wide association studies; microglia; neurodegeneration; neuroinflammation.

Fig. 1.

Disease-associated microglia surrounding Aβ plaques. Immunofluorescent stain of human Alzheimer's patient tissue demonstrates microglia (stained with DAM marker HLA-DR, red) surrounding Aβ plaques (gray). HLA is upregulated in microglia around plaques. The scale represents 50 μm.

Fig. 2.

Alzheimer’s risk genes are enriched in microglia over total cortex expression. Transcriptome data from Zhang et al. [24] was used to generate this heatmap of expression levels of each AD risk gene in the brain cortex (left) versus expression level in microglial cells (right). Data are displayed in frequency per kilobase million reads (FPKM).