Microglial dysfunction and NLRP3 inflammasome signaling in Alzheimer’s disease: mechanistic insights into neuroinflammation and neurodegeneration

Abstract

Alzheimer's disease (AD) is a progressively debilitating neurodegenerative condition characterized by the accumulation of amyloid-β (Aβ), tau pathology, synaptopathy, and neuron loss. Recent studies suggest that Neuroinflammation is a critical part of the disease process rather than an accompanying feature of the mentioned pathological changes. Microglia, the immune cells of the central nervous system, respond to amyloid-beta and pathological tau and exhibit functional alterations leading to the transition from their initial anti-inflammatory and neuroprotective function to chronic inflammation. Persistent activation of microglia is linked with the inability to clear abnormal proteins, excessive complement-dependent synaptic loss, secretion of cytokines, activation of astrocytes, and neuronal damage. Various inflammatory pathways play their roles, and one of the most prominent is the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome. The activation of the NLRP3 inflammasome leads to the recruitment of apoptosis-associated speck-like protein containing CARD (ASC) and caspase-1 activation, followed by interleukin-1β (IL-1β) and IL-18 maturation and gasdermin D (GSDMD) cleavage, contributing to pyroptosis and inflammatory processes. The current review will cover changing role of microglia in AD progression, interactions between Aβ, tau, and inflammatory signaling pathways as well as molecular mechanisms of NLRP3 Inflammasome activation. Furthermore, it will discuss new approaches that could be used for modulations of NLRP3 inflammasome signaling, including selective small molecule inhibition, caspase-1 targeting, natural compound use, repurposed drugs, and new drug delivery systems. Specifically, the ability to cross blood-brain barrier (BBB), safety, translational challenges, and dissimilarity between animal models and humans' AD will be discussed in this context. Overall, targeting dysregulated Neuroinflammation, including NLRP3 inflammasome activation, could serve as an alternative approach to existing protein-directed treatment methods.