Chapter Thirteen - The NLRP3 inflammasome as a bridge between neuro-inflammation in metabolic and neurodegenerative diseases

https://doi.org/10.1016/bs.irn.2020.03.023Get rights and content

Abstract

Evidence increasingly suggests that type 2 diabetes mellitus (T2DM) is a risk factor for neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD) and Parkinson's disease (PD). These diseases share many pathological processes, including oxidative stress, local inflammation/neuroinflammation and chronic, low-grade (systemic) inflammation, which are exacerbated by aging, a common risk factor for T2DM and NDDs. Here, we focus on the link between chronic inflammation driven by peripheral metabolic disease and how this may impact neurodegeneration in AD and PD. We review the relationship between these common pathological processes in AD and PD from the perspective of the “pro-inflammatory” signaling of the nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat- (LRR)-, and pyrin domain-containing protein 3 (NLRP3) inflammasome complex. Since the need for effective disease-modifying therapies in T2DM, AD and PD is significant, the relationship between these diseases is important as a positive clinical impact on one may benefit the others. We briefly consider how novel strategies may target neuro-inflammation and provide potential therapies for AD and PD.

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,

References (282)

  • K.R. Chaudhuri et al.

    National Institute for Clinical Excellence. Non-motor symptoms of Parkinson's disease: Diagnosis and management

    Lancet Neurology

    (2006)
  • L. Chen et al.

    NLRP3 inflammasome activation by mitochondrial reactive oxygen species plays a key role in long-term cognitive impairment induced by paraquat exposure

    Neurobiology of Aging

    (2015)
  • C. de Dios et al.

    Oxidative inactivation of amyloid beta-degrading proteases by cholesterol-enhanced mitochondrial stress

    Redox Biology

    (2019)
  • S.M. de la Monte et al.

    Brain metabolic dysfunction at the core of Alzheimer's disease

    Biochemical Pharmacology

    (2014)
  • F. Di Virgilio et al.

    The P2X7 receptor in infection and inflammation

    Immunity

    (2017)
  • H.B. Dodiya et al.

    Chronic stress-induced gut dysfunction exacerbates Parkinson's disease phenotype and pathology in a rotenone-induced mouse model of Parkinson's disease

    Neurobiology of Disease

    (2020)
  • G. Forloni et al.

    Beta-amyloid fragment potentiates IL-6 and TNF-alpha secretion by LPS in astrocytes but not in microglia

    Cytokine

    (1997)
  • L. Franchi et al.

    Differential requirement of P2X7 receptor and intracellular K + for caspase-1 activation induced by intracellular and extracellular bacteria

    The Journal of Biological Chemistry

    (2007)
  • R.P. Friedland et al.

    Alzheimer's disease: Anteriorposterior and lateral hemispheric alterations in cortical glucose utilization

    Neuroscience Letters

    (1985)
  • J. Fu et al.

    The impairment of glucose-stimulated insulin secretion in pancreatic β-cells caused by prolonged glucotoxicity and lipotoxicity is associated with elevated adaptive antioxidant response

    Food and Chemical Toxicology

    (2017)
  • Y. Gu et al.

    Circulating inflammatory biomarkers in relation to brain structural measurements in a non-demented elderly population

    Brain, Behavior, and Immunity

    (2017)
  • M. He et al.

    An acetylation switch of the NLRP3 inflammasome regulates aging-associated chronic inflammation and insulin resistance

    Cell Metabolism

    (2020)
  • Y. He et al.

    Mechanism and regulation of NLRP3 inflammasome activation

    Trends in Biochemical Sciences

    (2016)
  • B. Hooshmand et al.

    Serum insulin and cognitive performance in older adults: A longitudinal study

    The American Journal of Medicine

    (2019)
  • D. Aarsland et al.

    Cognitive decline in Parkinson disease

    Nature Reviews. Neurology

    (2017)
  • J.M. Abais et al.

    Redox regulation of NLRP3 inflammasomes: ROS as trigger or effector?

    Antioxidants & Redox Signaling

    (2015)
  • B. Adams et al.

    Parkinson's disease: A systemic inflammatory disease accompanied by bacterial inflammagens

    Frontiers in Aging Neuroscience

    (2019)
  • A. Alonso et al.

    Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments

    Proceedings of the National Academy of Sciences of the United States of America

    (2001)
  • Y. Aman et al.

    Enhancing mitophagy as a therapeutic approach for neurodegenerative disorders

    International Review of Neurobiology

    (2020)
  • S.E. Arnold et al.

    Brain insulin resistance in type 2 diabetes and Alzheimer disease: Concepts and conundrums

    Nature Reviews. Neurology

    (2018)
  • F.G. Bauernfeind et al.

    Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression

    Journal of Immunology

    (2009)
  • D.E. Befroy et al.

    Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients

    Diabetes

    (2007)
  • R.D. Bell et al.

    Apolipoprotein E controls cerebrovascular integrity via cyclophilin A

    Nature

    (2012)
  • D. Béraud et al.

    α-Synuclein alters toll-like receptor expression

    Frontiers in Neuroscience

    (2011)
  • F. Bian et al.

    CRP-induced NLRP3 inflammasome activation increases LDL transcytosis across endothelial cells

    Frontiers in Pharmacology

    (2019)
  • A.C. Birdsill et al.

    Low cerebral blood flow is associated with lower memory function in metabolic syndrome

    Obesity (Silver Spring)

    (2013)
  • Y. Birnbaum et al.

    Dipeptidyl peptidase-4 inhibition by Saxagliptin prevents inflammation and renal injury by targeting the Nlrp3/ASC inflammasome

    BMJ Open Diabetes Research & Care

    (2016)
  • Y. Birnbaum et al.

    Combined SGLT2 and DPP4 inhibition reduces the activation of the Nlrp3/ASC inflammasome and attenuates the development of diabetic nephropathy in mice with type 2 diabetes

    Cardiovascular Drugs and Therapy

    (2018)
  • K. Blennow et al.

    Blood-brain barrier disturbance in patients with Alzheimer's disease is related to vascular factors

    Acta Neurologica Scandinavica

    (1990)
  • D. Blum-Degen et al.

    Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer's and de novo Parkinson's disease patients

    Neuroscience Letters

    (1995)
  • M. Bozluolcay et al.

    Inflammatory hypothesis as a link between Alzheimer's disease and diabetes mellitus

    Geriatrics & Gerontology International

    (2016)
  • H. Braak et al.

    Neuroanatomy and pathology of sporadic Parkinson's disease

    Advances in Anatomy, Embryology, and Cell Biology

    (2009)
  • V. Braniste et al.

    The gut microbiota influences blood-brain barrier permeability in mice

    Science Translational Medicine

    (2014)
  • F. Brosseron et al.

    Body fluid cytokine levels in mild cognitive impairment and Alzheimer's disease: A comparative overview

    Molecular Neurobiology

    (2014)
  • G.C. Brown et al.

    Inflammatory neurodegeneration and mechanisms of microglial killing of neurons

    Molecular Neurobiology

    (2010)
  • J. Brown et al.

    TLR-signaling networks: An integration of adaptor molecules, kinases, and cross-talk

    Journal of Dental Research

    (2011)
  • I.L. Campbell et al.

    Trans-signaling is a dominant mechanism for the pathogenic actions of interleukin-6 in the brain

    The Journal of Neuroscience

    (2014)
  • C.A. Castellano et al.

    Lower brain 18F-fluorodeoxyglucose uptake but normal 11C-acetoacetate metabolism in mild Alzheimer's disease dementia

    Journal of Alzheimer's Disease

    (2015)
  • G. Cenini et al.

    Oxidative stress in neurodegenerative diseases: From a mitochondrial point of view

    Oxidative Medicine and Cellular Longevity

    (2019)
  • E. Cereda et al.

    Diabetes and risk of Parkinson's disease: A systematic review and meta-analysis

    Diabetes Care

    (2011)
  • Cited by (21)

    • Neuroprotective and anti-inflammatory phenylethanoid glycosides from the fruits of Forsythia suspensa

      2021, Bioorganic Chemistry
      Citation 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 Research
      Citation 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 Neurobiology
      Citation 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.

    View all citing articles on Scopus
    View full text