Inflammasome-Mediated Neuroinflammation: A Key Driver in Alzheimer's Disease Pathogenesis

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder predominantly affecting the elderly, characterized by memory loss, cognitive decline, and functional impairment. While hallmark pathological features include extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, increasing evidence points to chronic neuroinflammation as a key driver of disease progression. Among inflammatory mechanisms, the activation of the NLRP3 (nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome in microglia plays a pivotal role by amplifying neuroinflammatory cascades, exacerbating synaptic dysfunction, and accelerating neuronal loss. This review examines the molecular underpinnings of AD with a focus on NLRP3 inflammasome-mediated neuroinflammation, detailing the crosstalk between Aβ, tau pathology, and innate immune responses. Finally, we highlight emerging therapeutic strategies targeting NLRP3 inflammasome activation as promising avenues for mitigating neuroinflammation and slowing AD progression.

Keywords: Alzheimer’s disease; NLRP3 inflammasome; amyloid beta; cytokines; microglia activation; neurodegeneration; neuroinflammation; synaptic dysfunction; tau pathology; therapeutic targets.

Figure 1

Alternative splicing and processing of Amyloid Precursor Protein (APP) through amyloidogenic and non-amyloidogenic pathways. In the non-amyloidogenic pathway, APP is sequentially cleaved by α-secretase and γ-secretase. Cleavage by α-secretase produces soluble APPα (sAPPα) and a membrane-bound C-terminal fragment (CTFα or C83). Subsequent cleavage of C83 by γ-secretase generates non-toxic P3 peptides and the APP intracellular domain (AICD). In contrast, the amyloidogenic pathway involves the initial cleavage of APP by β-secretase, releasing soluble APPβ (sAPPβ) and generating the membrane-associated CTF99/89 fragment. γ-secretase then cleaves CTF99/89 to produce various Amyloid Beta (Aβ) peptides, predominantly Aβ40 and Aβ42, with Aβ42 being more prone to aggregation. Aggregated Aβ42 forms insoluble amyloid fibrils, leading to plaque deposition. This process also triggers kinase activation, resulting in the hyperphosphorylation of tau proteins and the subsequent formation of neurofibrillary tangles (NFTs), contributing to Alzheimer’s disease pathology.

Figure 2

Activation of the inflammasome cascade by the deposition of Aβ plaques and neurofibrillary tangles. The accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles in the brain triggers the recruitment of microglia around these pathological structures. This process initiates microglial activation and the subsequent stimulation of the NLRP3 inflammasome within these cells. Activated NLRP3 inflammasomes lead to the cleavage of pro-caspase-1 into its active form, caspase-1. Caspase-1 then processes pro-inflammatory cytokines pro-IL-1β and pro-IL-18 into their active forms. IL-1β serves as a potent pro-inflammatory mediator, while IL-18 promotes the production of interferon-gamma (IFN-γ), further amplifying the inflammatory response. These cytokines perpetuate neuroinflammation by activating additional microglia and astrocytes, creating a chronic inflammatory loop. Sustained inflammation ultimately contributes to synaptic dysfunction and neuronal degeneration, hallmark features of Alzheimer’s disease progression.