CD40 signaling regulates innate and adaptive activation of microglia in response to amyloid β‐peptide
Open accessAbstract
Although deposition of amyloid beta-peptide (Abeta) as Abeta plaques involves activation of microglia-mediated inflammatory responses, activated microglia ultimately fail to clear Abeta plaques in the brains of either Alzheimer's disease (AD) patients or AD mouse models. Mounting evidence suggests that chronic microglia-mediated immune response during Abeta deposition etiologically contributes to AD pathogenesis by promoting Abeta plaque formation. However, the mechanisms that govern microglia response in the context of cerebral Abeta/beta-amyloid pathology are not well understood. We show that ligation of CD40 by CD40L modulates Abeta-induced innate immune responses in microglia, including decreased microglia phagocytosis of exogenous Abeta(1-42) and increased production of pro-inflammatory cytokines. CD40 ligation in the presence of Abeta(1-42) leads to adaptive activation of microglia, as evidenced by increased co-localization of MHC class II with Abeta. To assess their antigen-presenting cell (APC) function, cultured microglia were pulsed with Abeta(1-42) in the presence of CD40L and co-cultured with CD4(+) T cells. Under these conditions, microglia stimulate T cell-derived IFN-gamma and IL-2 production, suggesting that CD40 signaling promotes the APC phenotype. These data provide a mechanistic explanation for our previous work showing decreased microgliosis associated with diminished cerebral Abeta/beta-amyloid pathology when blocking CD40 signaling in transgenic Alzheimer's mice.
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In vivo Aβ removal is critically dependent on microglial activation status.
“However, considerable evidence suggests that in vivo A removal is critically dependent on microglial activation status.33,44 -47”
From CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer's Disease Mouse Models (2010) · cites this paper as [44]
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- Authors
- Townsend, K. P., Town, T., Mori, T., Lue, L., Shytle, D., Sanberg, P. R., Morgan, D., Fernandez, F., Flavell, R. A., & Tan, J.
- Affiliations
- University of South Florida (US)
- Howard Hughes Medical Institute (US)
- Banner Sun Health Research Institute (US)
- Corresponding author
- Tan, Jun
- Venue
- European Journal of Immunology
- Publisher
- Wiley
- Published
- 2005-02-22
- Volume
- 35
- Issue
- 3
- Pages
- 901-910
- ISSN
- 0014-2980 (ISSN-L)
- 1521-4141
- OpenAlex
- W2050216330
- Cited by
- 121
- References
- 4
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 5 · 2022: 3 · 2021: 4 · 2020: 1 · 2019: 4 · 2018: 4 · 2017: 4 · 2015: 7 · 2014: 2 · 2013: 10 · 2012: 5
- FWCI
- 7.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- National Institutes of Health
- National Institute on Aging
- National Cancer Institute
- National Institute of Neurological Disorders and Stroke
- 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
- CD40 signaling, CD40 ligand, microglia, amyloid-beta, Alzheimer's disease, innate immunity, adaptive immunity, antigen presentation, MHC class II, phagocytosis, inflammatory cytokines, T cell activation, interferon-gamma, interleukin-2, microglial activation, neuroinflammation
- MeSH terms
- Alzheimer Disease, Animals, Histocompatibility Antigens Class II, Cells, Cultured, Disease Models, Animal, Flow Cytometry, Humans, Immunity, Innate, Microscopy, Fluorescence, Blotting, Western, Signal Transduction, Amyloid beta-Peptides, Microglia, Antigen Presentation, CD40 Antigens, CD40 Ligand, Mice
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