Abstract
Neurodegenerative diseases are neuronal disorders characterized by the loss of a large number of neurons in the human brain. Innate immunity-mediated neuroinflammation actively contributes to the onset and progression of neurodegenerative diseases. Inflammasomes are involved in the progression of the innate immune response and are responsible for the maturation of caspase-1 and inflammatory cytokines during neuroinflammation. The nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome, which is one of the most intensively investigated inflammasomes, has been reported to play a key role in neurodegenerative diseases. Here, we reviewed the mechanisms, role, and latest developments regarding the NLRP3 inflammasome with respect to three neurodegenerative diseases: Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Patient and animal model studies have found that abnormal protein aggregation of Aβ, synuclein, or copper–zinc superoxide dismutase-1 (SOD1), which are the main proteins expressed in the three diseases, respectively, can activate microglial cells, induce increased interleukin-1β (IL-1β) release, and activate the NLRP3 pathway, leading to neurodegeneration. In contrast, a deficiency of the components of the NLRP3 pathway may inhibit Aβ, synuclein, or SOD1-induced microglial activation. These studies indicate a positive correlation between NLRP3 levels and abnormal protein aggregation. However, in the case of ALS, not only microglia but also astrocytes express increased NLRP3 levels and contribute to activation of the NLRP3 pathway. In addition, in this review article, we also focus on the therapeutic implications of targeting novel inhibitors of the NLRP3 inflammasome or of novel drugs that mediate the NLRP3 pathway, which could play a role via NLRP3 in the treatment of neurodegenerative diseases.
Highlights
Neurodegenerative diseases are neuronal disorders characterized by the loss of a large number of neurons in the human brain, for example, Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease
The effects of inhibitors of caspase-1 or NLRP3 on Aβ deposits and behaviors in an AD model are reduced by decreasing the level of microglial pyroptosis. These findings suggest that NLRP3 and IL-1β play important roles in the pathophysiology of AD by regulating the pyroptosis, tau, or Thioredoxin-interacting protein (TXNIP) pathways
Inhibition of NLRP3 in animal models reduces the inflammatory response, decreases abnormal protein deposition, and corrects behavioral abnormalities associated with neurodegenerative diseases, suggesting the possibility of targeting NLRP3 inflammasome to treat such diseases
Summary
Neurodegenerative diseases are neuronal disorders characterized by the loss of a large number of neurons in the human brain, for example, Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease. Tenuigenin (a component of Polygala tenuifolia), Astragaloside IV (a component of Astragalus membranaceus), and bushenyizhi formula (composed of common Cnidium fruit, tree peony bark, ginseng root, Radix Polygoni Multiflori preparata, Barbary wolfberry fruit, and Fructus Ligustri Lucidi) were shown to significantly ameliorate DA neuron degeneration and alleviate motor impairment by suppressing NLRP3 inflammasome activation in the MPTP mouse model (Fan et al, 2017; Mo et al., 2018; Leng et al, 2019) Based on these findings, medicines and exogenous compounds that target the NLRP3 inflammasome may offer novel therapeutic directions for treating PD. In ALS, microglia and astrocytes switch from a neuroprotective to a proinflammatory phenotype by releasing potentially neurotoxic cytokines
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