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Cited by 34Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsInflammasome and immune disorders

Interleukin-1β mediated amyloid plaque clearance is independent of CCR2 signaling in the APP/PS1 mouse model of Alzheimer's disease

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Rivera-Escalera, Fátima, Matousek, Sarah B., Ghosh, Simantini, Olschowka, John A., O’Banion, M. Kerry·2014·Neurobiology of Disease
DOI 10.1016/j.nbd.2014.05.018PMC PMC4120473
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Abstract

Neuroinflammation is a key component of Alzheimer's disease (AD) pathogenesis. Particularly, the proinflammatory cytokine interleukin-1 beta (IL-1β) is upregulated in human AD and believed to promote amyloid plaque deposition. However, studies from our laboratory have shown that chronic IL-1β overexpression in the APPswe/PSEN1dE9 (APP/PS1) mouse model of AD ameliorates amyloid pathology, increases plaque-associated microglia, and induces recruitment of peripheral immune cells to the brain parenchyma. To investigate the contribution of CCR2 signaling in IL-1β-mediated amyloid plaque clearance, seven month-old APP/PS1/CCR2(-/-) mice were intrahippocampally transduced with a recombinant adeno-associated virus serotype 2 containing the cleaved form of human IL-1β (rAAV2-IL-1β). Four weeks after rAAV2-IL-1β transduction, we found significant reductions in 6E10 and Congo red staining of amyloid plaques that was confirmed by decreased levels of insoluble Aβ1-42 and Aβ1-40 in the inflamed hippocampus. Bone marrow chimeric studies confirmed the presence of infiltrating immune cells following IL-1β overexpression and revealed that dramatic reduction of CCR2(+) peripheral mononuclear cell recruitment to the inflamed hippocampus did not prevent the ability of IL-1β to induce amyloid plaque clearance. These results suggest that infiltrating CCR2(+) monocytes do not contribute to IL-1β-mediated amyloid plaque clearance.

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  • IL-1β does not influence Aβ production.

    “This is consistent with our previously published data showing that IL-1β does not influence Aβ production [4, 6, 7, 28].”

    From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [28]

    The Results (pages not provided) report that IL-1β overexpression did not alter APP levels or processing in the hippocampus of APP/PS1 mice, including BACE activity and β-CTF products. This supports unchanged Aβ production in that experimental setting, but the paper does not directly measure production rates or establish that IL-1β never influences Aβ production more generally. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • There was minimal recruitment of CD45hi peripheral immune cells (CD11b+ and CD11b−) in APP/PS1-Phe mice.

    “In agreement with our previous observations [28, 30] there was minimal recruitment of CD45hi peripheral immune cells (CD11b+ and CD11b−) in APP/PS1-Phe mice”

    From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [28]

    The Results (page unavailable) report no GFP+ peripheral-derived cells in control-vector hippocampi of APP/PS1/CCR2−/− mice, and the Discussion reports no evidence of peripheral plaque-associated microglia in APP/PS1 mice without IL-1 induction. These findings support minimal recruitment in control conditions, but the paper does not establish that both CD45hi/CD11b+ and CD45hi/CD11b− populations were minimally recruited specifically in APP/PS1-Phe mice. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Recruited myeloid cells are not essential for IL-1β-mediated fibrillar Aβ clearance.

    “This is in agreement with our previous studies showing that recruited myeloid cells are not essential for IL-1β-mediated fibrillar Aβ clearance [28]”

    From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [28]

    The Results report that IL-1β reduced Congo Red-stained fibrillar amyloid plaques even when CCR2+ monocyte recruitment was prevented. The Discussion concludes that infiltrating CCR2+ mononuclear cells are not essential, but the claim broadens that finding to recruited myeloid cells generally. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Disrupting CCR2 signaling and recruitment of BMD-mononuclear phagocytes did not alter the ability of IL-1β to reduce amyloid plaque burden.

    “However, disrupting CCR2 signaling and recruitment of BMD-mononuclear phagocytes did not alter the ability of IL-1β to reduce amyloid plaque burden [28].”

    From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [28]

  • CCR2+ mononuclear cells are recruited to the inflamed hippocampus and associate with amyloid plaques in a CCR2-dependent manner.

    “Previously we showed that CCR2+ mononuclear cells are recruited to the inflamed hippocampus and associate with amyloid plaques in a CCR2-dependent manner [28].”

    From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [28]

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Cites

Flagged first, then by citations

Research works printed but not linked: 29

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Authors
Rivera-Escalera, F., Matousek, S. B., Ghosh, S., Olschowka, J. A., & O’Banion, M. K.
Affiliations
University of Rochester Medicine (US)
Corresponding author
O’Banion, M. Kerry
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2014-09
Volume
69
Pages
124-133
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2014.05.018
PMC
PMC4120473
OpenAlex
W2079738010
Cited by
34
References
8
Citations by year
2026: 2 · 2025: 2 · 2023: 2 · 2022: 3 · 2021: 5 · 2020: 3 · 2019: 5 · 2018: 1 · 2017: 4 · 2016: 4 · 2015: 2 · 2014: 1
FWCI
2.44
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Disease (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute of Health (RO1 AG030149, T32 NS007489, F31 AG031667)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
IL-1β, amyloid plaque clearance, Alzheimer's disease, APP/PS1 mice, neuroinflammation, microglia, bone marrow chimeras, amyloid-beta 42, Aβ40, AAV gene delivery, hippocampus
MeSH terms
Alzheimer Disease, Animals, Disease Models, Animal, Hippocampus, Humans, Leukocytes, Mononuclear, Mice, Transgenic, Peptide Fragments, Neuroimmunomodulation, Signal Transduction, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Transplantation Chimera, Interleukin-1beta, Presenilin-1, Receptors, CCR2, Plaque, Amyloid

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