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Cited by 57Inflammasome and immune disordersAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

Identification of inflammasome signaling proteins in neurons and microglia in early and intermediate stages of Alzheimer's disease

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Vontell, Regina T., de Rivero Vaccari, Juan Pablo, Sun, Xiaoyan, Gultekin, Sakir Humayun, Bramlett, Helen M., Dietrich, W. Dalton, Keane, Robert W.·2023·Brain Pathology
DOI 10.1111/bpa.13142PMC PMC10307529
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Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease that destroys memory and cognitive function. Inflammasome activation has been suggested to play a critical role in the neuroinflammatory response in AD progression, but the cell‐type expression of inflammasome proteins in the brain has not been fully characterized. In this study, we used samples from the hippocampus formation, the subiculum, and the entorhinal cortex brain from 17 donors with low‐level AD pathology and 17 intermediate AD donors to assess the expression of inflammasome proteins. We performed analysis of hippocampal thickness, β‐amyloid plaques, and hyperphosphorylated tau to ascertain the cellular pathological changes that occur between low and intermediate AD pathology. Next, we determined changes in the cells that express the inflammasome sensor proteins NOD‐like receptor proteins (NLRP) 1 and 3, and caspase‐1. In addition, we stained section with IC100, a humanized monoclonal antibody directed against the inflammasome adaptor protein apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC), and a commercially available anti‐ASC antibody. Our results indicate that hippocampal cortical thickness did not significantly change between low and intermediate AD pathology, but there was an increase in pTau and β‐amyloid clusters in intermediate AD cases. NLRP3 was identified mainly in microglial populations, whereas NLRP1 was seen in neuronal cytoplasmic regions. There was a significant increase of ASC in neurons labeled by IC100, whereas microglia in the hippocampus and subiculum were labeled with the commercial anti‐ASC antibody. Caspase‐1 was present in the parenchyma in the CA regions where amyloid and pTau were identified. Together, our results indicate increased inflammasome protein expression in the early pathological stages of AD, that IC100 identifies neurons in early stages of AD and that ASC expression correlates with Aβ and pTau in postmortem AD brains.

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  • Evidence for activation of functional NLRP3 inflammasomes has been detected in early and intermediate stages of Alzheimer's disease from studies of post-mortem brains.

    “Evidence for activation of functional NLRP3 inflammasomes has been detected in early and intermediate stages of AD from studies of post-mortem brains.”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [76]

    The Results section (‘NLRP3 is mainly present in microglia-like structures’; page unavailable) identifies NLRP3 in post-mortem tissue from low and intermediate AD cases. The Discussion also reports previous evidence of NLRP3 inflammasome activation in human post-mortem brains. However, this study measures inflammasome-protein expression and location; it does not establish that the NLRP3 inflammasomes it detected were functional and activated in both stages. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • The NLRP3 inflammasome might not be active at the mildly cognitively impaired stage of Alzheimer's disease.

    “suggesting that the NLRP3 inflammasome might not be active at this stage of disease [75, 76].”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [76]

    The Results section reports NLRP3 expression in microglia in low and intermediate pathological stages of AD, but expression does not establish whether the inflammasome is active. The Discussion mentions elevated ASC and IL-18 in patients with mild cognitive impairment; it does not assess NLRP3 activity in those patients. Searches for mild cognitive impairment and NLRP3 activation found no passage supporting the proposed lack of activity. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • In monocytes from mildly cognitively impaired individuals, NLRP3 and caspase-1 were not co-localized and IL-18/IL-1β secretion was not detected.

    “In these monocytes, NLRP3 and caspase-1 were also not co-localized and IL-18/IL-1β secretion was not detected”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [76]

    The Results sections on NLRP3 and caspase-1 examine postmortem hippocampal tissue, not monocytes from people with mild cognitive impairment. A Discussion passage mentions elevated serum IL-18 in such patients, but does not address secretion by their monocytes. Searches for monocytes, NLRP3–caspase-1 co-localization, and IL-18/IL-1β secretion found no passage establishing the claimed findings; page numbers were not available in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • In monocytes isolated from mildly cognitively impaired individuals, only an increase in NLRP3 levels, but not in ASC or caspase-1, was observed.

    “only an increase in NLRP3 levels, but not in ASC or caspase-1, was observed in monocytes isolated from mildly cognitively impaired (MCI) individuals.”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [76]

    The Abstract and Discussion (pages unavailable) describe inflammasome proteins in postmortem brain neurons and microglia, not monocytes isolated from people with mild cognitive impairment. Searches for monocytes, MCI, and the claimed NLRP3-versus-ASC/caspase-1 pattern found no passage addressing that comparison. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

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Authors
Vontell, R. T., de Rivero Vaccari, J. P., Sun, X., Gultekin, S. H., Bramlett, H. M., Dietrich, W. D., & Keane, R. W.
Affiliations
  • University of Miami (US)
  • Department of Neurological Surgery and The Miami Project to Cure Paralysis University of Miami Miller School of Medicine Miami Florida USA
Corresponding author
Vontell, Regina T.
ORCID
Venue
Brain Pathology
Publisher
Wiley
Published
2022-12-29
Volume
33
Issue
4
Pages
e13142-e13142
ISSN
  • 1015-6305 (ISSN-L)
  • 1750-3639
DOI
10.1111/bpa.13142
PMC
PMC10307529
OpenAlex
W4313280131
Cited by
57
References
6
Citations by year
2026: 19 · 2025: 15 · 2024: 14 · 2023: 8 · 2022: 1
FWCI
3.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain Pathology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institute of Neurological Disorders and Stroke (R01NS11396901)
  • Florida Department of Health (21A13)
  • National Institute on Aging (1RF1NS12557801)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, inflammasome, neuroinflammation, microglia, neurons, NLRP1, NLRP3, caspase-1, ASC, amyloid plaques, hyperphosphorylated tau, hippocampus, subiculum, entorhinal cortex, early Alzheimer's disease, postmortem brain
MeSH terms
Alzheimer Disease, Humans, Neurons, Amyloid beta-Peptides, Microglia, Neurodegenerative Diseases, Caspase 1, Plaque, Amyloid, Inflammasomes

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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