Targeting microglial autophagic degradation in NLRP3 inflammasome-mediated neurodegenerative diseases

Neuroinflammation is considered as a detrimental factor in neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), etc. Nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3), the most well-studied inflammasome, is abundantly expressed in microglia and has gained considerable attention. Misfolded proteins are characterized as the common hallmarks of neurodegenerative diseases due to not only their induced neuronal toxicity but also their effects in over-activating microglia and the NLRP3 inflammasome. The activated NLRP3 inflammasome aggravates the pathology and accelerates the progression of neurodegenerative diseases. Emerging evidence indicates that microglial autophagy plays an important role in the maintenance of brain homeostasis and the negative regulation of NLRP3 inflammasome-mediated neuroinflammation. The excessive activation of NLRP3 inflammasome impairs microglial autophagy and further aggravates the pathogenesis of neurodegenerative diseases. In this review article, we summarize and discuss the NLRP3 inflammasome and its specific inhibitors in microglia. The crucial role of microglial autophagy and its inducers in the removal of misfolded proteins, the clearance of damaged mitochondria and reactive oxygen species (ROS), and the degradation of the NLRP3 inflammasome or its components in neurodegenerative diseases are summarized. Understanding the underlying mechanisms behind the sex differences in NLRP3 inflammasome-mediated neurodegenerative diseases will help researchers to develop more targeted therapies and increase our diagnostic and prognostic abilities. In addition, the superiority of the combined use of microglial autophagy inducers with the specific inhibitors of the NLRP3 inflammasome in the inhibition of NLRP3 inflammasome-mediated neuroinflammation requires further preclinical and clinical validations in the future.