Neurodegenerative Disease and the NLRP3 Inflammasome

Abstract

The prevalence of neurodegenerative disease has increased significantly in recent years, and with a rapidly aging global population, this trend is expected to continue. These diseases are characterised by a progressive neuronal loss in the brain or peripheral nervous system, and generally involve protein aggregation, as well as metabolic abnormalities and immune dysregulation. Although the vast majority of neurodegeneration is idiopathic, there are many known genetic and environmental triggers. In the past decade, research exploring low-grade systemic inflammation and its impact on the development and progression of neurodegenerative disease has increased. A particular research focus has been whether systemic inflammation arises only as a secondary effect of disease or is also a cause of pathology. The inflammasomes, and more specifically the NLRP3 inflammasome, a crucial component of the innate immune system, is usually activated in response to infection or tissue damage. Dysregulation of the NLRP3 inflammasome has been implicated in the progression of several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases. This review aims to summarise current literature on the role of the NLRP3 inflammasome in the pathogenesis of neurodegenerative diseases, and recent work investigating NLRP3 inflammasome inhibition as a potential future therapy.

Keywords: Alzheimer's disease; NLRP3 inflammasome; Parkinson’s disease; inflammation; neurodegenerative disease; neuroinflammation.

FIGURE 1

Common dysregulated mechanisms underlying neurodegenerative diseases. Demonstrating the similarities between the dysregulated mechanisms underlying each of the neurodegenerative diseases covered in this review. These overlapping disease mechanisms suggest that similar therapeutics could be utilised to treat several of these conditions.

FIGURE 2

NLRP3 inflammasome activation in neurodegenerative disorders. The NLRP3 inflammasome assembles in response to two signals; toll-like receptor 4 (TLR4) stimulation by LPS induces the NF-κβ-mediated transcription of pro-IL-1β and pro-IL-18, and stimuli such as P2X7 receptor-facilitated potassium (K⁺) efflux trigger NLRP3 inflammasome activation. The activated NLRP3 inflammasome recruits an adaptor protein, apoptosis-associated speck-like protein containing a CARD (ASC), and oligomerises to activate caspase-1, which cleaves pro-IL-1β and pro-IL-18 into their active forms. Disease-related proteins can also activate the NLRP3 inflammasome. Phagocytosis of fibrillar β-amyloid (Aβ) (Alzheimer’s disease) causes NLRP3 inflammasome activation via lysosomal damage and cathepsin B release. Aβ also binds to ASC specks released during inflammasome activation, increasing the formation of Aβ oligomers. Tau monomers and oligomers (Alzheimer’s disease) activate the NLRP3 inflammasome, which, in turn, affects tau hyperphosphorylation and aggregation. Phagocytosis of aggregated α-synuclein (Parkinson’s disease) results in NLRP3 inflammasome activation, and uptake of aggregated α-synuclein, mediated by Fyn kinase and the class B scavenger receptor CD36, facilitates LPS-independent inflammasome priming. α-synuclein is also associated with mitochondrial dysfunction, including mitochondrial DNA (mtDNA) disturbances. Mutant SOD1 (ALS) acts as a DAMP to activate the NLRP3 inflammasome. Transactive response DNA-binding protein-43 (TDP-43) (ALS) causes CD14-induced NF-κβ activation, and triggers mtDNA release. In prion diseases, aggregated and fibrillar forms of the neurotoxic PrP-derived peptide (PrP106–126) are involved in NLRP3 inflammasome priming, via triggering NF-κβ signaling, and activation. This NLRP3 inflammasome activation can be prevented by the NLRP3 specific inhibitor, MCC950, increasing the extracellular K⁺ concentration to prevent K⁺ efflux, prevention of P2X7 receptor activation by CD39-mediated ATP hydrolysis, inhibition of mitochondrial reactive oxygen species (mROS) by N-acetyl-l-cysteine and the anti-inflammatory hormone 17β-estradiol. The broad caspase inhibitor, zVAD-fmk, and the recombinant IL-1 receptor antagonist, anakinra, both reduce the downstream effects of NLRP3 activation in disease.