Identification of glia phenotype modulators based on select glial function regulatory signaling pathways

Introduction: Despite the considerable social and economic burden on the healthcare system worldwide due to neurodegenerative diseases, there are currently few disease-altering treatment options for many of these conditions. Therefore, new approaches for both prevention and intervention for neurodegenerative diseases are urgently required. Microglia-mediated neurotoxicity is one of the pathologic hallmarks common to Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Current therapeutic approaches to target microglia-mediated neurotoxicity are focused on the identification of glia phenotype modulators (GPMs), which can inhibit the ‘classical’ pro-inflammatory and neurotoxic phenotypes of microglia. Areas covered: This article reviews selected microglial molecular targets and pathways involved in either neurotoxicity or neuroprotection and how their identification. Expert opinion: Microglial activation and their signaling pathways have important implications in the neurotoxicity and brain disorders. Pharmacological modulation of microglial activation may serve as a potential therapeutic approach for targeting microglia-mediated neurotoxicity. However, given that microglia change their activation states depending on the timing, stage, and severity of disease, and even aging, the appropriate window should be considered for this approach to be clinically effective. In the future, the identification of unknown extracellular signals and intracellular molecular switches that control phenotypic shifts may facilitate the development of novel therapeutics targeting microglia-mediated neurotoxicity.