Chapter Thirteen - The NLRP3 inflammasome as a bridge between neuro-inflammation in metabolic and neurodegenerative diseases
Introduction
A strong link exists between type 2 diabetes mellitus (T2DM) and neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD) and Parkinson's disease (PD). These diseases share many pathological processes, including oxidative stress (OxS), local inflammation/neuroinflammation and chronic, low-grade (systemic) inflammation. Metabolic disorders cause OxS, which triggers inflammatory responses via activation of redox sensitive transcription factors and stress signaling pathways that feedback positively to exacerbate OxS, inflammation and peripheral tissue damage. Consequent chronic inflammation damages the vascular endothelium and disrupts the blood-brain barrier (BBB). This increases the brain's vulnerability to systemic oxidative, inflammatory and other, potentially toxic, mediators. These processes are exacerbated by aging, a common risk factor for T2DM, AD and PD.
Here, we review the relationship between OxS and chronic inflammation and neuroinflammation in T2DM, AD and PD from the perspective of innate immune signaling, nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat- (LRR)-, and pyrin domain-containing protein 3 (NLRP3) inflammasome. We will review how peripheral metabolic diseases and chronic inflammation can impact the brain, the role of the NLRP3 inflammasome in AD and PD, and how a therapeutic impact on any of these diseases might offer mutual benefits based on their mechanistically intertwined pathological processes.
Section snippets
NLRP3 inflammasome formation requires priming and activation
The inflammasomes are important components of the innate immune system. First described almost two decades ago by Martinon, Burns, and Tschopp (2002), the large, multi-protein inflammasome complexes are pattern recognition receptors (PPRs) and innate immune cell sensors for Pathogen-Associated Molecular Patterns (PAMPs), Microbial-Associated Molecular Patterns (MAMPs) and Danger-Associated Molecular Patterns (DAMPs) associated with cellular dysfunction, and trigger cytokine gene transcription.
The NLRP3 inflammasome, chronic inflammation and endothelial dysfunction
Pro-inflammatory cytokines are associated with the development of T2DM and consequent chronic inflammation that contributes to endothelial dysfunction. This may involve the NLRP3 inflammasome. The NLRP3, ASC and caspase-1 proteins are expressed in cultured mouse microvascular endothelial cells (Xia et al., 2014). C-reactive protein, another T2DM-associated cytokine, has been shown to upregulate NF-κB activity, induce expression of pro-IL-1β and NLRP3, and activate the NLRP3 inflammasome in
Pathology of Alzheimer's disease
Alzheimer's disease starts years before clinical symptoms of progressive cognitive impairment and episodic memory loss appear (Lane et al., 2018). It progresses through three stages: in preclinical AD, only biomarkers are evident (Sperling et al., 2011); in mild cognitive impairment (MCI) cognitive deficits, but no functional impairment are apparent (Albert et al., 2011); and, in AD dementia a decline in two or more cognitive domains has reached a stage where functioning at work or daily
Pathology of Parkinson's disease
Parkinson's disease is complex, progressive and influenced by genetic and environmental factors as yet of unknown etiology (Schapira and Jenner, 2011). Idiopathic PD is considered a movement disorder, characterized by bradykinesia, resting tremor, and muscles and joint rigidity. The severe loss of dopaminergic neurons in the substantia nigra and subsequent depletion of dopamine in the striatum are often associated with development of motor symptoms (Hornykiewicz, 2001; Obeso et al., 2008).
The NLRP3 inflammasome: A target for novel therapeutic approaches in Alzheimer's and Parkinson's diseases?
Evidence clearly demonstrates pathological commonalities and metabolic disturbances in T2DM and NDDs that may be mediated by OxS and neuro-inflammation. This opens the field to novel strategies to treat NDDs.
Type 2 diabetes is a risk factor for neurodegenerative diseases
Evidence suggests that T2DM is a risk factor associated with AD and PD and this is supported by the beneficial impact of antidiabetic therapies that are under evaluation in AD and PD.
Metabolic and neurodegenerative diseases share common risk factors
Type 2 diabetes mellitus has a complex and multifactorial etiology, as do AD and PD. Aging is the major risk factor for AD (Xia et al., 2018) and PD (Jenner et al., 2013), and a major risk factor for T2DM (Palmer et al., 2019). The classical hallmarks of aging (e.g., mitochondrial dysfunction and redox imbalance,
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High glucose levels accelerate atherosclerosis via NLRP3-IL/ MAPK/NF-κB-related inflammation pathways
2024, Biochemical and Biophysical Research CommunicationsNeuroprotective and anti-inflammatory phenylethanoid glycosides from the fruits of Forsythia suspensa
2021, Bioorganic ChemistryCitation Excerpt :Multiple investigations have proved that neuroinflammation underlies diverse neurodegenerative diseases, including Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease, amyotrophic lateral sclerosis and Huntington’s disease, of which Alzheimer’s disease and Parkinson’s disease are the first and second most prevalent age-related neurodegenerative disorders in the world. Increasing evidence today suggests that neuroinflammation is not only a later consequence but also could be an early trigger of the pathology [1–4]. However, the clinical therapies available for the treatment of neuroinflammation associated diseases nowadays have massive trouble with their efficiency and safety [5,6].
Chromosomal damage measured by the cytokinesis block micronucleus cytome assay in diabetes and obesity - A systematic review and meta-analysis
2020, Mutation Research - Reviews in Mutation ResearchCitation Excerpt :Overweight and Obesity (one of the main risk factors for the development of type 2 diabetes) can be starting points for further disease development in later life, such as cancer, kidney disease, diabetes and particularly cardiovascular disease [40,41]. Even diseases related to cognitive decline (Alzheimer’s, dementia) are linked to poor blood glucose control, insulin resistance and obesity [42,43]. Many of the possible consequences of overweight and/or diabetes are linked to reduced quality of life, loss of years in good health, accelerated aging, disability and dependency on others, all of which increase socio-economic and healthcare costs [44–46].
Status and future directions of clinical trials in Parkinson's disease
2020, International Review of NeurobiologyCitation Excerpt :Glucose metabolism is dysregulated (Dunn et al., 2014) and peripheral blood cells exhibit mitochondrial dysfunction and increased glycolysis (Smith et al., 2018). Moreover, PD and type 2 diabetes mellitus (T2DM) are bi-directional risk factors (Söderbom and Zeng, 2020) indicating a metabolic component to PD. Esterline et al. (2018) have suggested that the lack of metabolic flexibility in cells due to nutritional overload in T2DM interferes with mitochondrial dynamics and lysosomal function, leading to accumulation of dysfunctional mitochondria and impaired neuronal bioenergetics and so should also be investigated in PD.