Inflammasomes as therapeutic targets for <scp>A</scp>lzheimer's disease

White, Charles A.; Lawrence, Catherine B.; Brough, David; Rivers-Auty, Jack

doi:10.1111/bpa.12478

Cited by 121 publications

(84 citation statements)

References 173 publications

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“…One recent study reported a decrease in A20 mRNA levels in the blood of PD patients (Perga et al, ) similar to that reported in chronic inflammatory diseases (Gilli et al, ), supporting the potential use of A20 as a biomarker. During the last decade, the NLRP3 inflammasome has emerged as a promising pharmacological target for the prevention and treatment of a number of immune‐related diseases, including cancer, type II diabetes, rheumatoid arthritis and AD (Çimen et al, 2016; Coll et al, ; Lamkanfi & Dixit, ; White, Lawrence, Brough, & Rivers‐Auty, ). Strategies for controlling inflammasome activity are already being considered in clinical trials for some of these disorders, and might, if successful, be extended to subgroups of PD patients presenting aberrant NLRP3 signaling.…”

Section: Discussionmentioning

confidence: 99%

Parkin deficiency modulates NLRP3 inflammasome activation by attenuating an A20‐dependent negative feedback loop

Mouton-Liger

Rosazza

Sepúlveda-Díaz

et al. 2018

Glia

110

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Neuroinflammation and mitochondrial dysfunction, key mechanisms in the pathogenesis of Parkinson's disease (PD), are usually explored independently. Loss‐of‐function mutations of PARK2 and PARK6, encoding the E3 ubiquitin protein ligase Parkin and the mitochondrial serine/threonine kinase PINK1, account for a large proportion of cases of autosomal recessive early‐onset PD. PINK1 and Parkin regulate mitochondrial quality control and have been linked to the modulation of innate immunity pathways. We report here an exacerbation of NLRP3 inflammasome activation by specific inducers in microglia and bone marrow‐derived macrophages from Park2−/− and Pink1−/− mice. The caspase 1‐dependent release of IL‐1β and IL‐18 was, therefore, enhanced in Park2−/− and Pink1−/− cells. This defect was confirmed in blood‐derived macrophages from patients with PARK2 mutations and was reversed by MCC950, which specifically inhibits NLRP3 inflammasome complex formation. Enhanced NLRP3 signaling in Parkin‐deficient cells was accompanied by a lack of induction of A20, a well‐known negative regulator of the NF‐κB pathway recently shown to attenuate NLRP3 inflammasome activity. We also found an inverse correlation between A20 abundance and IL‐1β release, in human macrophages challenged with NLRP3 inflammasome inducers. Overall, our observations suggest that the A20/NLRP3‐inflammasome axis participates in the pathogenesis of PARK2‐linked PD, paving the way for the exploration of its potential as a biomarker and treatment target.

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Section: Discussionmentioning

confidence: 99%

Parkin deficiency modulates NLRP3 inflammasome activation by attenuating an A20‐dependent negative feedback loop

Mouton-Liger

Rosazza

Sepúlveda-Díaz

et al. 2018

Glia

110

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“…38 Moreover, in vitro experiments suggested an anti-inflammatory effect of AChEI on atherosclerosis. 39 As inflammation is important for AD and dementia, 40 a possible modulatory effect of AChEI on inflammation might result in decreased mortality rates in patients treated with antidementia drugs. Unfortunately, the present study was not powered to explore the different causes of death driven by antidementia drugs, and further studies are needed to address this issue.…”

Section: Discussionmentioning

confidence: 99%

Association of Antidementia Drugs and Mortality in Community-Dwelling Frail Older Patients With Dementia: The Role of Mortality Risk Assessment

Polidori

Veronese

Giancristofaro

et al. 2018

Journal of the American Medical Directors Association

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Objective: To evaluate whether treatment with antidementia drugs is associated with reduced mortality in older patients with different mortality risk at baseline. Design: Retrospective. Setting: Community-dwelling. Participants: A total of 6818 older people who underwent a Standardized Multidimensional Assessment Schedule for Adults and Aged Persons (SVaMA) evaluation to determine accessibility to homecare services or nursing home admission from 2005 to 2013 in the Padova Health District, Italy were included. Measurements: Mortality risk at baseline was calculated by the Multidimensional Prognostic Index (MPI), based on information collected with the SVaMA. Participants were categorized to have mild (MPI-SVaMA-1), moderate (MPI-SVaMA-2), and high (MPI-SVaMA-3) mortality risk. Propensity score-adjusted hazard ratios (HR) of 2-year mortality were calculated according to antidementia drug treatment. Results: Patients treated with antidementia drugs had a significant lower risk of death than untreated patients (HR 0.82; 95% confidence interval [CI] 0.73–0.92 and 0.56; 95% CI 0.49–0.65 for patients treated less than 2 years and more than 2 years treatment, respectively). After dividing patients according to their MPI-SVaMA grade, antidementia treatment was significantly associated with reduced mortality in the MPI-SVaMA-1 mild (HR 0.71; 95% CI 0.54–0.92) and MPI-SVaMA-2 moderate risk (HR 0.61; 95% CI 0.40–0.91, matched sample), but not in the MPI-SVaMA-3 high risk of death. Conclusions: This large community-dwelling patient study suggests that antidementia drugs might contribute to increased survival in older adults with dementia with lower mortality risk.

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“…To date, several advances have been made in the identification of exogenous compounds that may block IL-1 signaling or serve as inhibitors of NLRP3 inflammasome activation (White et al, 2017; see Figure 3); however, most compounds are in the early stages of development.…”

Section: Targeting the Nlrp3 Inflammasome For The Treatment Of Neurolmentioning

confidence: 99%

NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies

Song

Pei

Yao

et al. 2017

Front. Cell. Neurosci.

353

275

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Neuroinflammation has been identified as a causative factor of multiple neurological diseases. The nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome, a subcellular multiprotein complex that is abundantly expressed in the central nervous system (CNS), can sense and be activated by a wide range of exogenous and endogenous stimuli such as microbes, aggregated and misfolded proteins, and adenosine triphosphate, which results in activation of caspase-1. Activated caspase-1 subsequently leads to the processing of interleukin-1β (IL-1β) and interleukin-18 (IL-18) pro-inflammatory cytokines and mediates rapid cell death. IL-1β and IL-18 drive inflammatory responses through diverse downstream signaling pathways, leading to neuronal damage. Thus, the NLRP3 inflammasome is considered a key contributor to the development of neuroinflammation. In this review article, we briefly discuss the structure and activation the NLRP3 inflammasome and address the involvement of the NLRP3 inflammasome in several neurological disorders, such as brain infection, acute brain injury and neurodegenerative diseases. In addition, we review a series of promising therapeutic approaches that target the NLRP3 inflammasome signaling including anti-IL-1 therapy, small molecule NLRP3 inhibitors and other compounds, however, these approaches are still experimental in neurological diseases. At present, it is plausible to generate cell-specific conditional NLRP3 knockout (KO) mice via the Cre system to investigate the role of the NLRP3 inflammasome, which may be instrumental in the development of novel pharmacologic investigations for neuroinflammation-associated diseases.

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Inflammasomes as therapeutic targets for Alzheimer's disease

Cited by 121 publications

References 173 publications

Parkin deficiency modulates NLRP3 inflammasome activation by attenuating an A20‐dependent negative feedback loop

Parkin deficiency modulates NLRP3 inflammasome activation by attenuating an A20‐dependent negative feedback loop

Association of Antidementia Drugs and Mortality in Community-Dwelling Frail Older Patients With Dementia: The Role of Mortality Risk Assessment

NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies

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