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Cited by 351Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsInflammasome and immune disorders

Systemic inflammation impairs microglial Aβ clearance through NLRP3 inflammasome

Open access
Tejera, Dario, Mercan, Dilek, Sanchez‐Caro, Juan M, Hanan, Mor, Greenberg, David, Soreq, Hermona, Latz, Eicke, Golenbock, Douglas +1 more·2019·The EMBO Journal
DOI 10.15252/embj.2018101064PMC PMC6717897
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Abstract

Alzheimer's disease is the most prevalent type of dementia and is caused by the deposition of extracellular amyloid-beta and abnormal tau phosphorylation. Neuroinflammation has emerged as an additional pathological component. Microglia, representing the brain's major innate immune cells, play an important role during Alzheimer's. Once activated, microglia show changes in their morphology, characterized by a retraction of cell processes. Systemic inflammation is known to increase the risk for cognitive decline in human neurogenerative diseases including Alzheimer's. Here, we assess for the first time microglial changes upon a peripheral immune challenge in the context of aging and Alzheimer's in vivo, using 2-photon laser scanning microscopy. Microglia were monitored at 2 and 10 days post-challenge by lipopolysaccharide. Microglia exhibited a reduction in the number of branches and the area covered at 2 days, a phenomenon that resolved at 10 days. Systemic inflammation reduced microglial clearance of amyloid-beta in APP/PS1 mice. NLRP3 inflammasome knockout blocked many of the observed microglial changes upon lipopolysaccharide, including alterations in microglial morphology and amyloid pathology. NLRP3 inhibition may thus represent a novel therapeutic target that may protect the brain from toxic peripheral inflammation during systemic infection.

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Authors
Tejera, D., Mercan, D., Sanchez‐Caro, J. M., Hanan, M., Greenberg, D., Soreq, H., Latz, E., Golenbock, D., & Heneka, M. T.
Affiliations
  • University Hospital Bonn (DE)
  • Hebrew University of Jerusalem (IL)
  • University of Massachusetts Chan Medical School (US)
Corresponding author
Heneka, Michael T
ORCID
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
2019-07-30
Volume
38
Issue
17
Pages
e101064-e101064
ISSN
  • 0261-4189 (ISSN-L)
  • 1460-2075
DOI
10.15252/embj.2018101064
PMC
PMC6717897
OpenAlex
W2964855216
Cited by
351
References
83
Citations by year
2026: 27 · 2025: 51 · 2024: 54 · 2023: 52 · 2022: 56 · 2021: 64 · 2020: 41 · 2019: 6
FWCI
18.49
Type
journal article
Language
en
Open access
Licence
Locations
  • The EMBO Journal (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Open Repository and Bibliography (University of Luxembourg) (submittedVersion, other-oa)
  • DZNE Pub (submittedVersion, other-oa)
Funders
  • Deutsche Forschungsgemeinschaft (DFG)
  • Deutsches Zentrum für Luft‐ und Raumfahrt (01EW1508)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
Alzheimer's disease, systemic inflammation, microglia, amyloid-beta clearance, NLRP3 inflammasome, lipopolysaccharide, microglial morphology, APP/PS1 mice, neuroinflammation, aging
MeSH terms
NLR Family, Pyrin Domain-Containing 3 Protein, Aging, Alzheimer Disease, Animals, Disease Models, Animal, Humans, Inflammation, Lipopolysaccharides, Amyloid beta-Peptides, Microglia, Microscopy, Confocal, Mice, Gene Knockout Techniques

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