Inflammasomes in Alzheimer's Progression: Nrf2 as a Preventive Target

Abstract

Current knowledge about Alzheimer's disease highlights the accumulation of β-amyloid plaques (Aβ1-42) and neurofibrillary tangles composed of hyperphosphorylated Tau, which lead to the loss of neuronal connections. Microglial activation and the release of inflammatory mediators play a significant role in the progression of Alzheimer's pathology. Recent advances have identified the involvement of inflammasomes, particularly NOD-like receptor NLR family pyrin domain containing 3 (NLRP3), whose activation promotes the release of proinflammatory cytokines and triggers pyroptosis, exacerbating neuroinflammation. Aggregates of Aβ1-42 and hyperphosphorylated Tau have been shown to activate these inflammasomes, while the apoptosis-associated speck-like protein (ASC) components form aggregates that further accelerate Aβ aggregation. Defects in the autophagic clearance of inflammasomes have also been implicated in Alzheimer's disease, contributing to sustained inflammation. This review explores strategies to counteract inflammation in Alzheimer's, emphasizing the degradation of ASC specks and the inhibition of NLRP3 inflammasome activation. Notably, the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor emerges as a promising therapeutic target due to its dual role in mitigating oxidative stress and directly inhibiting NLRP3 inflammasome formation. By reducing inflammasome-driven inflammation, Nrf2 offers significant potential for addressing the neuroinflammatory aspects of Alzheimer's disease.

Keywords: ASC; Alzheimer’s; Aβ proteins; Nrf2; inflammasome NLRP3; inflammation.

Figure 1

Phosphorylation of Tau at serine and threonine residues by proline-directed and non-proline-directed kinases. Proline-directed kinases, such as glycogen synthase kinase-3 beta (GSK-3β) and cyclin dependent kinase 5 (CDK5), are involved in the aberrant hyperphosphorylation of Tau and the progression of Alzheimer’s disease.

Figure 2

NLRP3 activation flowchart. The activation of the NOD-like receptor NLR family pyrin domain containing 3 (NLRP3) inflammasome occurs in two distinct steps. In the first step, Toll-like receptors (TLRs) are triggered by damage-associated molecular patterns (DAMPs), pathogen-associated molecular patterns (PAMPs), or hyaluronan-binding glycoproteins (HAMPs). This activation results in the translocation of nuclear factor kappa B (NF-κB) to the nucleus, where it enhances the transcription of inflammasome components, including pro-interleukin-1β (pro-IL-1β) and pro-interleukin-18 (pro-IL-18). In the second step, a secondary signal, typically derived from DAMPs such as adenosine triphosphate (ATP), Tau protein intracellular neurofibrillary tangles (NFTs), or amyloid-beta aggregates, induces the oligomerization of the NLRP3. The formation of these pores triggers inflammation by releasing mature interleukins and allows for water to enter the cell. Finally, pyroptosis occurs, and all cytoplasmic contents are released. As a consequence, this process promotes neuronal inflammation in Alzheimer’s disease (AD).

Figure 3

Molecular mechanisms that regulate death by pyroptosis induced by the accumulation of AB and Tau in Alzheimer’s disease (AD). (A) The β-amyloid (Aβ) aggregates (DAMPs) stimulate TLR receptors and the translocation of nuclear factor kappa B (NF-κB) to the cell nucleus, which, in turn, increases the transcription of the inflammasome components and expression of pro-interleukin-1β (pro-IL-1β) and pro-interleukin-18 (pro-IL-18). (B) Aberrant AD proteins are phagocytosed by microglia. The phagocytosed proteins are taken to the lysosome. There, they can disrupt the lysosomal membrane and cause assembly of the inflammasome. (C) Activation of the inflammasome leads to cleavage of pro-caspase 1 to caspase 1. Caspase 1 cleaves gasdermin D, which allows for the formation of the lysis pore. Caspase 1 also cleaves pro-IL-1B and pro-IL-18 to IL-1B and IL-18. (D) The insertion of the cleaved gasdermin N-terminal fragment into the plasma membrane creates oligomeric pores and allows for the release of proinflammatory products such as IL-1β and IL-18 to the extracellular space. Pore formation also induces water influx into the cell, cell swelling, and osmotic cell lysis, which induces further inflammation and hypertension by releasing more inflammatory products from the intracellular space. (E) As a consequence of all of the above processes, the osmotic pressure increases and normal cellular activities cease, and finally the cell undergoes an explosive death called pyroptosis.