Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice
Abstract
We have shown that interaction of CD40 with CD40L enables microglial activation in response to amyloid-beta peptide (Abeta), which is associated with Alzheimer's disease (AD)-like neuronal tau hyperphosphorylation in vivo. Here we report that transgenic mice overproducing Abeta, but deficient in CD40L, showed decreased astrocytosis and microgliosis associated with diminished Abeta levels and beta-amyloid plaque load. Furthermore, in the PSAPP transgenic mouse model of AD, a depleting antibody against CD40L caused marked attenuation of Abeta/beta-amyloid pathology, which was associated with decreased amyloidogenic processing of amyloid precursor protein (APP) and increased circulating levels of Abeta. Conversely, in neuroblastoma cells overexpressing wild-type human APP, the CD40-CD40L interaction resulted in amyloidogenic APP processing. These findings suggest several possible mechanisms underlying mitigation of AD pathology in response to CD40L depletion, and validate the CD40-CD40L interaction as a target for therapeutic intervention in AD.
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The interaction of CD40 on microglia and CD40L on T cells promotes pro-inflammatory microglial cell activation in response to Aβ.
“A study has shown that the interaction of CD40 (expressed on the surface of microglia) and CD40L (T-cell receptor) promotes pro-inflammatory microglial cell activation in response to Aβ[166].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [166]
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- Authors
- Tan, J., Town, T., Crawford, F., Mori, T., DelleDonne, A., Crescentini, R., Obregon, D., Flavell, R. A., & Mullan, M. J.
- Affiliations
- University of South Florida (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Mullan, Michael J.
- Venue
- Nature Neuroscience
- Published
- 2002-10-28
- Volume
- 5
- Issue
- 12
- Pages
- 1288-1293
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W2036094153
- Cited by
- 217
- References
- 6
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 2 · 2021: 6 · 2020: 7 · 2019: 9 · 2018: 1 · 2017: 4 · 2016: 2 · 2015: 10 · 2014: 12 · 2013: 15 · 2012: 15
- FWCI
- 4.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of South Florida
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- CD40 ligand, CD40-CD40L interaction, Alzheimer's disease, amyloid-beta, amyloid plaques, microglial activation, astrocyte activation, tau hyperphosphorylation, APP processing, anti-CD40L antibody, neuroblastoma cells, therapeutic target
- MeSH terms
- Alzheimer Disease, Animals, Astrocytes, Brain, Disease Models, Animal, Female, Gliosis, Male, Neurons, Tumor Cells, Cultured, Down-Regulation, Up-Regulation, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Microglia, Mice, Knockout, CD40 Antigens, CD40 Ligand, Mice, Plaque, Amyloid
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