Microglia–immune communication in Amyotrophic Lateral Sclerosis

Abstract

Neuroinflammation, consisted of both neuroprotective and neurotoxic reactions by activated glial cells and the infiltrated immune cells, is involved in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). Microglia are resident innate immune cells in central nervous system, and the activation phenotypes in healthy and diseased brain have been extensively examined through RNA–Seq. As an activation phenotype of microglia, M1/M2 hypothesis of microglia has recently been reconsidered by the new concept, disease–associated microglia (DAM). DAM is defined by a small set of deregulated genes, and commonly observed in neurodegenerative diseases including AD, ALS, and aging. We revisited the gene expression profiling of microglia isolated from App^NL–G–F knock–in (Amyloid β) mice, rTg4510 (Tau) mice, and SOD1^G93A (ALS) mice. Comparison of microglia transcriptome revealed that a loss of homeostatic microglia is correlated with a severity of neurodegeneration, suggesting that a loss of homeostatic microglia seems to be more important than DAM phenotype. Moreover, the systemic environment affects and alters the microglial phenotype and disease outcome, revealed by the study using SOD1^G93A mice with distinct genetic backgrounds (C57Bl/6 and Balb/c).

In summary, microglia and immune communication actively contributes to neurodegeneration in ALS and AD through research using rodent models, and accumulating research results indicate glial cells and neuroinflammation as viable therapeutic targets for neurodegenerative diseases.