Inflammasome signalling in brain function and neurodegenerative disease
Abstract
The mammalian CNS is an intricate and fragile structure, which on one hand is open to change in order to store information, but on the other hand is vulnerable to damage from injury, pathogen invasion or neurodegeneration. During senescence and neurodegeneration, activation of the innate immune system can occur. Inflammasomes are signalling complexes that regulate cells of the immune system, which in the brain mainly includes microglial cells. In microglia, the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome becomes activated when these cells sense proteins such as misfolded or aggregated amyloid-β, α-synuclein and prion protein or superoxide dismutase, ATP and members of the complement pathway. Several other inflammasomes have been described in microglia and the other cells of the brain, including astrocytes and neurons, where their activation and subsequent caspase 1 cleavage contribute to disease development and progression.
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NLRP3 inflammasome is a multiprotein complex that leads to secretion of IL-1β and IL-18 upon activation, and its aberrant activation has been extensively linked to AD.
“NLRP3 inflammasome is a multiprotein complex that leads to the secretion of the proinflammatory cytokines IL-1β and IL-18 upon its activation, and its aberrant activation has been extensively linked to AD13.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [13]
NLRP3 inflammasomes are currently the best characterized inflammasomes and are predominantly expressed by microglia in the central nervous system.
“NLRP3 inflammasomes are currently the best characterized inflammasomes and are predominantly expressed by microglia in the CNS [55].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [55]
Pro-caspase-1 undergoes proximity-induced autoproteolysis, leading to active caspase-1 processing pro-IL-1β and pro-IL-18 into their mature forms and subsequent secretion.
“Pro-caspase-1 then undergoes proximity-induced autoproteolysis, which leads to active caspase-1 processing pro-IL-1β and pro-IL-18 into their mature forms IL-1β and IL-18 and the subsequent secretion of these cytokines [55, 58, 61–63]”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [55]
Inflammasomes are part of the innate immune system that coordinate host defense response against pathogens and host-derived danger signals that communicate cellular stress or toxicity.
“Inflammasomes are a part of the innate immune system that coordinate host defense response against pathogens and host-derived “danger” signals that communicate cellular stress or toxicity [19, 54, 55].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [55]
Increased baseline activation of the NLRP3 inflammasome in aging may predispose the brain to neurodegenerative diseases, in which neuroinflammation is a common feature.
“Therefore, increased baseline activation of the NLRP3 inflammasome in aging may predispose the brain to neurodegenerative diseases, in which neuroinflammation is a common feature [55].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [55]
Elevated levels of IL-1β in the brain can induce neuroinflammation, neurotoxicity and learning and memory impairment.
“Elevated levels of IL-1β in the brain can itself induce neuroinflammation, neurotoxicity and learning and memory impairment [55, 74].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [55]
NLRP3 inflammasome accumulates inside microglia upon activation, promoting cleavage and activity of caspase-1 and release of IL-1β.
“NLRP3 inflammasome has been proven to accumulate inside microglia upon activation, promoting cleavage and activity of caspase-1 and release of IL-1β [160].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [160]
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- Authors
- Heneka, M. T., McManus, R. M., & Latz, E.
- Affiliations
- University of Bonn (DE)
- Corresponding author
- Heneka, Michael T.
- Venue
- Nature Reviews Neuroscience
- Published
- 2018-09-11
- Volume
- 19
- Issue
- 10
- Pages
- 610-621
- ISSN
- 1471-003X (ISSN-L)
- 1471-0048
- OpenAlex
- W2890670389
- Cited by
- 836
- References
- 22
- Citations by year
- 2026: 105 · 2025: 104 · 2024: 122 · 2023: 101 · 2022: 134 · 2021: 120 · 2020: 93 · 2019: 53 · 2018: 4
- FWCI
- 6.62
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-02-11)
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion)
- DZNE Pub (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- NLRP3 inflammasome, microglia, neurodegenerative diseases, caspase-1, amyloid-beta, alpha-synuclein, prion protein, superoxide dismutase, complement pathway, astrocytes, neurons, neuroinflammation
- MeSH terms
- Animals, Brain, Humans, Signal Transduction, Neurodegenerative Diseases, Inflammasomes
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