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Cited by 293Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsInflammasome and immune disorders

Acute systemic inflammation exacerbates neuroinflammation in Alzheimer's disease: IL‐1β drives amplified responses in primed astrocytes and neuronal network dysfunction

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Lopez‐Rodriguez, Ana Belen, Hennessy, Edel, Murray, Carol L., Nazmi, Arshed, Delaney, Hugh J., Healy, Dáire, Fagan, Steven G., Rooney, Michael +8 more·2021·Alzheimer's & Dementia
DOI 10.1002/alz.12341PMC PMC8874214

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Abstract

Neuroinflammation contributes to Alzheimer's disease (AD) progression. Secondary inflammatory insults trigger delirium and can accelerate cognitive decline. Individual cellular contributors to this vulnerability require elucidation. Using APP/PS1 mice and AD brain, we studied secondary inflammatory insults to investigate hypersensitive responses in microglia, astrocytes, neurons, and human brain tissue. The NLRP3 inflammasome was assembled surrounding amyloid beta, and microglia were primed, facilitating exaggerated interleukin‐1β (IL‐1β) responses to subsequent LPS stimulation. Astrocytes were primed to produce exaggerated chemokine responses to intrahippocampal IL‐1β. Systemic LPS triggered microglial IL‐1β, astrocytic chemokines, IL‐6, and acute cognitive dysfunction, whereas IL‐1β disrupted hippocampal gamma rhythm, all selectively in APP/PS1 mice. Brains from AD patients with infection showed elevated IL‐1β and IL‐6 levels. Therefore, amyloid leaves the brain vulnerable to secondary inflammation at microglial, astrocytic, neuronal, and cognitive levels, and infection amplifies neuroinflammatory cytokine synthesis in humans. Exacerbation of neuroinflammation to produce deleterious outcomes like delirium and accelerated disease progression merits careful investigation in humans.

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  • IL1B is a major mediator of AD-associated neuroinflammatory signaling.

    “BDNF is a major regulator of neuronal survival and synaptic plasticity and has been linked to synaptic dysfunction in AD (Gao et al., 2022; Lu et al., 2014), whereas IL1B is a major mediator of AD-associated neuroinflammatory signaling (Lopez-Rodriguez et al., 2021).”

    From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as Lopez-Rodriguez et al., 2021

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Authors
Lopez‐Rodriguez, A. B., Hennessy, E., Murray, C. L., Nazmi, A., Delaney, H. J., Healy, D., Fagan, S. G., Rooney, M., Stewart, E., Lewis, A., de Barra, N., Scarry, P., Riggs‐Miller, L., Boche, D., Cunningham, M. O., & Cunningham, C.
Affiliations
  • School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute and Trinity College Institute of Neuroscience Trinity College Dublin Dublin Rep. of Ireland
  • Trinity College Dublin (IE)
  • University of Southampton (GB)
Corresponding author
Cunningham, Colm
ORCID
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2021-06-03
Volume
17
Issue
10
Pages
1735-1755
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
DOI
10.1002/alz.12341
PMC
PMC8874214
OpenAlex
W3165442994
Cited by
293
References
32
Citations by year
2026: 60 · 2025: 70 · 2024: 65 · 2023: 48 · 2022: 27 · 2021: 16 · 2020: 2 · 2019: 4 · 2018: 1
FWCI
15.66
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • ePrints Soton (University of Southampton) (acceptedVersion)
  • Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
Funders
National Institutes of Health (R01AG050626)
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, neuroinflammation
MeSH terms
Alzheimer Disease, Amyloid, Animals, Astrocytes, Brain, Hippocampus, Humans, Inflammation, Mice, Transgenic, Neurons, Cytokines, Microglia, Mice, Interleukin-1beta, Inflammasomes

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