A good deal of evidence points to increased inflammatory activation of microglia in the brain, and consequent chronic inflammation of brain tissue, as an important component of neurodegenerative conditions. Some of these inflammatory microglia are senescent, and their clearance has been shown to be helpful in animal models, but the broader problem is an imbalance between pro-inflammatory M1 microglia and anti-inflammatory M2 microglia. A number of options exist if the goal is to shift the balance, from clearance and regeneration of all microglia via CSFR1 inhibition to various mechanisms that might encourage microglia to preferentially adopt the M2 state.
Microglia-mediated neuroinflammation is a common feature shared by various neurodegenerative diseases. Neuroinflammatory includes microglial activation, and microglia could polarize into either M1 pro-inflammatory phenotype or M2 anti-inflammatory phenotype in response to different micro-environmental disturbances, which are called classical activation and alternative activation, respectively. M1 microglia release inflammatory cytokines and chemokines, resulting in inflammation and neuronal death. However, tissue maintenance and repair are associated with alternative activation of M2 microglia. M1 microglia induce inflammation and neurotoxicity, while M2 microglia induce anti-inflammatory and neuroprotection, both of which are involved in the pathogenesis of neurodegenerative diseases, therefore microglia act as a double-edged sword in neurodegenerative diseases.
It's impossible to repair or regenerate damaged neurons by current drugs nowadays once neurodegenerative diseases occur or even before the onset of diseases, but current drugs could alleviate disease-related symptoms by restricting the extent of neuroinflammation. Fortunately, the balance between microglia M1/M2 polarization has a promising therapeutic prospect in the pathogenesis of neurodegenerative diseases. However, previous studies have shown that several M1 inhibitive agents are unhelpful.
As inhibiting M1 microglia alone is not enough, promoting M2 microglia activation simultaneously might also be required for treating neurodegenerative diseases. Promoting microglia polarization shift from M1 to M2 phenotype may be a more prospective strategy in the therapy of neurodegenerative diseases. Activated microglia is also a double-edged sword in other central nervous system diseases such as ischemic stroke, spinal cord injury, and traumatic brain injury. There have been many studies about modulation of microglia polarization from M1 to M2 in these diseases, which may provide many interesting ideas in neurodegenerative diseases.