Chronic Neuron-Specific Tumor Necrosis Factor-Alpha Expression Enhances the Local Inflammatory Environment Ultimately Leading to Neuronal Death in 3xTg-AD Mice
Open accessAbstract
Inflammatory mediators, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta, appear integral in initiating and/or propagating Alzheimer's disease (AD)-associated pathogenesis. We have previously observed a significant increase in the number of mRNA transcripts encoding the pro-inflammatory cytokine TNF-alpha, which correlated to regionally enhanced microglial activation in the brains of triple transgenic mice (3xTg-AD) before the onset of overt amyloid pathology. In this study, we reveal that neurons serve as significant sources of TNF-alpha in 3xTg-AD mice. To further define the role of neuronally derived TNF-alpha during early AD-like pathology, a recombinant adeno-associated virus vector expressing TNF-alpha was stereotactically delivered to 2-month-old 3xTg-AD mice and non-transgenic control mice to produce sustained focal cytokine expression. At 6 months of age, 3xTg-AD mice exhibited evidence of enhanced intracellular levels of amyloid-beta and hyperphosphorylated tau, as well as microglial activation. At 12 months of age, both TNF receptor II and Jun-related mRNA levels were significantly enhanced, and peripheral cell infiltration and neuronal death were observed in 3xTg-AD mice, but not in non-transgenic mice. These data indicate that a pathological interaction exists between TNF-alpha and the AD-related transgene products in the brains of 3xTg-AD mice. Results presented here suggest that chronic neuronal TNF-alpha expression promotes inflammation and, ultimately, neuronal cell death in this AD mouse model, advocating the development of TNF-alpha-specific agents to subvert AD.
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AAV2 selectively transduces neurons and its use in the CNS is well characterized.
“AAV2 selectively transduces neurons and its use in the CNS is well characterized [34–36].”
From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [35]
Overexpression of TNF-α in 3xTg mice ultimately led to neuronal death marked by loss of NeuN-positive neurons in the injected region.
“These ultimately led to neuronal death marked by a loss of NeuN-positive neurons in the injected region [148].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [148]
Overexpression of TNF-α in 3xTg mice led to enhancement of the local inflammatory environment, increased intracellular Aβ levels and tau hyperphosphorylation.
“overexpression of TNF-α in 3xTg mice led to enhancement of the local inflammatory environment, increased intracellular Aβ levels and tau hyperphosphorylation.”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [148]
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- Authors
- Janelsins, M. C., Mastrangelo, M. A., Park, K. M., Sudol, K. L., Narrow, W. C., Oddo, S., LaFerla, F. M., Callahan, L. M., Federoff, H. J., & Bowers, W. J.
- Affiliations
- University of Rochester Medicine (US)
- University of California, Irvine (US)
- Corresponding author
- Bowers, William J.
- ORCID
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2008-12
- Volume
- 173
- Issue
- 6
- Pages
- 1768-1782
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC2626388
- OpenAlex
- W2008423159
- Cited by
- 220
- References
- 43
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 12 · 2023: 8 · 2022: 14 · 2021: 26 · 2020: 16 · 2019: 20 · 2018: 14 · 2017: 10 · 2016: 12 · 2015: 9 · 2014: 8 · 2013: 13 · 2012: 16
- FWCI
- 7.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (F31NS049995, R01-AG020204, R01-AG023593, R01-AG026328)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- TNF-α, Alzheimer's disease, 3xTg-AD mice, neuroinflammation, microglial activation, amyloid-beta, hyperphosphorylated tau, TNF receptor 2, neuronal cell death
- MeSH terms
- Dependovirus, Alzheimer Disease, Animals, Brain, Genetic Vectors, Humans, Inflammation, Macrophages, Mice, Transgenic, Neurons, Tumor Necrosis Factor-alpha, Amyloid beta-Peptides, tau Proteins, Microglia, Transgenes, Mice
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