The common end stage pathology of neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) is neuronal death. Several decades of basic research have focused on investigating the mechanisms underlying neuronal death and dysfunction. Accumulating studies showed that neuroinflammation is correlated with disease progression, suggesting that non-neuronal cells such as microglia, astrocytes and immune cells in addition to neurons play a role in disease pathogenesis. However, how each cell types contributes to neuroinflammation and consequently leading to disease pathogenesis remains elusive. In this proposal, we will study ALS, a neurodegenerative disease associated with motor neuron degeneration, neuroinflammation, muscle weakness and paralysis. It remains elusive how neuroinflammation contributes to the disease process and particularly how microglia respond to changes in the brain and whether they play a protective or toxic role in disease pathogenesis in ALS. Microglia are the resident macrophages that rapidly respond to an injury by migrating toward the injury site, secreting cytokines, engulfing and removing damaged cells or neurons. Various microglial subtypes with different function exist in the nervous system. In addition, microglial subtypes are different between brain regions, and also the subtypes change with age. Little is known about the microglial subtypes that are associated with ALS. Therefore, we will identify the unique microglial subtypes that are associated with ALS using our newly established ALS mouse model. In addition, we will determine the role of a specific microglial subtype that has phagocytic characteristics. The findings from these studies will reveal and advance knowledge into the disease process involving both neurons and microglia in ALS. The knowledge will have implications for the understanding of other neurodegenerative diseases including AD and PD.