Microglial NLRP3 Inflammasomes in Alzheimer's Disease Pathogenesis: From Interaction with Autophagy/Mitophagy to Therapeutics

The nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, discovered 20 years ago, is crucial in controlling innate immune reactions in Alzheimer's disease (AD). By initiating the release of inflammatory molecules (including caspases, IL-1 beta, and IL-18), the excessively activated inflammasome complex in microglia leads to chronic inflammation and neuronal death, resulting in the progression of cognitive deficiencies. Even though the involvement of NLRP3 has been implicated in neuroinflammation and widely explored in several studies, there are plenty of controversies regarding its precise roles and activation mechanisms in AD. Another prominent feature of AD is impairment in microglial autophagy, which can be either the cause or the consequence of NLRP3 activation and contributes to the aggregation of misfolded proteins and aberrant chronic inflammatory state seen in the disease course. Studies also demonstrate that intracellular buildup of dysfunctional and damaged mitochondria due to defective mitophagy enhances inflammasome activation, further suggesting that restoration of impaired autophagy and mitophagy can effectively suppress it, thereby reducing inflammation and protecting microglia and neurons. This review is primarily focused on the role of NLRP3 inflammasome in the etiopathology of AD, its interactions with microglial autophagy/mitophagy, and the latest developments in NLRP3 inflammasome-targeted therapeutic interventions being implicated for AD treatment.