Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases

Abstract

One of the most striking hallmarks shared by various neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease (AD), and amyotrophic lateral sclerosis, is microglia-mediated neuroinflammation. Increasing evidence indicates that microglial activation in the central nervous system is heterogeneous, which can be categorized into two opposite types: M1 phenotype and M2 phenotype. Depending on the phenotypes activated, microglia can produce either cytotoxic or neuroprotective effects. In this review, we focus on the potential role of M1 and M2 microglia and the dynamic changes of M1/M2 phenotypes that are critically associated with the neurodegenerative diseases. Generally, M1 microglia predominate at the injury site at the end stage of disease, when the immunoresolution and repair process of M2 microglia are dampened. This phenotype transformation is very complicated in AD due to the phagocytosis of regionally distributed β-amyloid (Aβ) plaque and tangles that are released into the extracellular space. The endogenous stimuli including aggregated α-synuclein, mutated superoxide dismutase, Aβ, and tau oligomers exist in the milieu that may persistently activate M1 pro-inflammatory responses and finally lead to irreversible neuron loss. The changes of microglial phenotypes depend on the disease stages and severity; mastering the stage-specific switching of M1/M2 phenotypes within appropriate time windows may provide better therapeutic benefit.

Detection of Cyclooxygenase-1 in Activated Microglia During Amyloid Plaque Progression: PET Studies in Alzheimer’s Disease Model Mice

“…Increasing evidence indicates that switching of the microglial phenotype from M2 to M1 occurs in the brain of AD and plays a significant role in disease progression (30). Targeting neuroinflammatory events in AD, primarily microglial activation, remains debatable as a promising therapeutic option because microglial phagocytosis may also contribute to the clearance of Ab plaques from brain tissue.…”

Alzheimer’s disease as an inflammatory disease

“…However, these cells show high levels of diversity and plasticity and their classification into an M1 or M2 polarized state may be an oversimplification (14,33,34). Recently, it has been proposed that microglia switch continuously between phenotypes (35,36).…”

“…In contrast, M2 microglia express anti-inflammatory molecules, such as IL-10 and transforming growth factor (TGF)-β, and extracellular matrix molecules (39). In addition, it has been proposed that M1 microglia predominate at the site of injury under pathological situations, whereas M2 microglia appear later at a stage more related to repair processes (34). In most cases, microglia in AD patients exhibit mixed activation phenotypes.…”

“…In this regard, it has also been hypothesized that aging leads to the dysfunction or dystrophia of these cells (34). Nevertheless, a larger reduction in process length and arborized area in AD compared to aged-matched control microglia has recently been described (41).…”

Potential Modes of Intercellular Alpha-Synuclein Transmission

“…Previous studies have shown that lysosomal impairment is observed in PD, in both sporadic and familial cases, although this work has focused on neurons . It is conceivable that α-syn could attract and activate microglia which fail to completely clear α-syn and potentially cause neurodegeneration themselves through an excessive pro-inflammatory response (Tang and Le, 2015).…”