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Cited by 232Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsIntracerebral and Subarachnoid Hemorrhage Research

Expression of inflammatory genes induced by beta-amyloid peptides in human brain endothelial cells and in Alzheimer's brain is mediated by the JNK-AP1 signaling pathway

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Vukic, Vanja, Callaghan, Debbie, Walker, Douglas, Lue, Lih-Fen, Liu, Qing Yan, Couraud, Pierre-Oliver, Romero, Ignacio A., Weksler, Babette +2 more·2009·Neurobiology of Disease
DOI 10.1016/j.nbd.2008.12.007PMC PMC2720310
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Abstract

Alzheimer's disease (AD) is characterized by accumulation and deposition of Abeta peptides in the brain. Abeta deposition in cerebral vessels occurs in many AD patients and results in cerebral amyloid angiopathy (AD/CAA). Abeta deposits evoke neuro- and neurovascular inflammation contributing to neurodegeneration. In this study, we found that exposure of cultured human brain endothelial cells (HBEC) to Abeta(1-40) elicited expression of inflammatory genes MCP-1, GRO, IL-1beta and IL-6. Up-regulation of these genes was confirmed in AD and AD/CAA brains by qRT-PCR. Profiling of 54 transcription factors indicated that AP-1 was strongly activated not only in Abeta-treated HBEC but also in AD and AD/CAA brains. AP-1 complex in nuclear extracts from Abeta-treated HBEC bound to AP-1 DNA-binding sequence and activated the reporter gene of a luciferase vector carrying AP-1-binding site from human MCP-1 gene. AP-1 is a dimeric protein complex and supershift assay identified c-Jun as a component of the activated AP-1 complex. Western blot analyses showed that c-Jun was activated via JNK-mediated phosphorylation, suggesting that as a result of c-Jun phosphorylation, AP-1 was activated and thus up-regulated MCP-1 expression. A JNK inhibitor SP600125 strongly inhibited Abeta-induced c-Jun phosphorylation, AP-1 activation, AP-1 reporter gene activity and MCP-1 expression in cells stimulated with Abeta peptides. The results suggested that JNK-AP1 signaling pathway is responsible for Abeta-induced neuroinflammation in HBEC and Alzheimer's brain and that this signaling pathway may serve as a therapeutic target for relieving Abeta-induced inflammation.

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  • MCP-1 is highly expressed in cerebral endothelial cells from AD patients.

    “MCP-1, which has been shown to be highly expressed in the cerebral endothelial cells from AD patients.471”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [471]

    The Results section, “The expression of inflammatory genes was up-regulated in AD brain” (page unavailable), reports significantly increased MCP-1 expression in AD and AD/CAA brain tissue. The Discussion also reports MCP-1 induction in cultured human brain endothelial cells exposed to Aβ. Neither finding establishes that MCP-1 is highly expressed specifically in cerebral endothelial cells taken from AD patients. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • In vitro treatment of endothelial cells with Aβ induced expression of IFN-γ, IL-6, IL-1β, and CD40, increasing secretion of MCP-1.

    “In vitro treatment of endothelial cells with Aβ induced expression of multiple inflammatory molecules, including IFN-γ, IL-6, IL-1β, and CD40,470,471 increasing the secretion of monocyte chemoattractant, MCP-1, which has been shown to be highly expressed in the cerebral endothelial cells from AD patients.471”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [471]

    The Results section ('Aβ1–40 induces inflammatory gene expression in HBEC'; page not available) reports increased IL-6 and IL-1β expression in Aβ-treated human brain endothelial cells and increased MCP-1 release into culture medium. Neither that section nor the Discussion's list of induced molecules includes IFN-γ or CD40, so the full list attributed to this paper is not supported. (LLM, conf=0.88)

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Authors
Vukic, V., Callaghan, D., Walker, D., Lue, L.-F., Liu, Q. Y., Couraud, P.-O., Romero, I. A., Weksler, B., Stanimirovic, D. B., & Zhang, W.
Affiliations
  • University of Ottawa (CA)
  • Institute for Biological Sciences (CA)
  • Banner Sun Health Research Institute (US)
  • Centre National de la Recherche Scientifique (FR)
  • The Open University (GB)
  • Weill Cornell Medicine (US)
Corresponding author
Zhang, Wandong
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2009-04
Volume
34
Issue
1
Pages
95-106
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2008.12.007
PMC
PMC2720310
OpenAlex
W2050737600
Cited by
232
References
7
Citations by year
2026: 8 · 2025: 11 · 2024: 17 · 2023: 18 · 2022: 13 · 2021: 11 · 2020: 17 · 2019: 11 · 2018: 20 · 2017: 11 · 2016: 11 · 2015: 17 · 2014: 9 · 2013: 11 · 2012: 7
FWCI
10.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Disease (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • NPARC (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Open Research Online - ORO (The Open University) (submittedVersion)
Funders
  • University of Ottawa
  • National Institute on Aging (P30-AG-19610, P30AG019610)
  • National Institute of Neurological Disorders and Stroke (R01NS049075)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
Keywords
Alzheimer's disease, amyloid-beta, Aβ(1-40), cerebral amyloid angiopathy, neuroinflammation, brain endothelial cells, JNK signaling, AP-1 transcription factor, c-Jun phosphorylation, MCP-1, SP600125, IL-1β, interleukin-6, GRO, therapeutic target
MeSH terms
Alzheimer Disease, Anthracenes, Brain, Cells, Cultured, Enzyme Inhibitors, Humans, Peptide Fragments, Phosphorylation, Signal Transduction, Interleukin-6, Up-Regulation, Amyloid beta-Peptides, Proto-Oncogene Proteins c-jun, Transcription Factor AP-1, Chemokine CCL2, Endothelial Cells, MAP Kinase Kinase 4, Interleukin-1beta, Chemokine CXCL1

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