Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTg-AD mice

Michelle C. Janelsins, Michael A. Mastrangelo, Keigan M. Park, Kelly L. Sudol, Wade C. Narrow, Salvatore Oddo, Frank M. LaFerla, Linda M. Callahan, Howard J. Federoff, William J. Bowers

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135 Scopus citations

Abstract

Inflammatory mediators, such as tumor necrosis factor-α (TNF-α) 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-α, 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-α in 3xTg-AD mice. To further define the role of neuronally derived TNF-α during early AD-like pathology, a recombinant adeno-associated virus vector expressing TNF-α 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-β 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-α and the AD-related transgene products in the brains of 3xTg-AD mice. Results presented here suggest that chronic neuronal TNF-α expression promotes inflammation and, ultimately, neuronal cell death in this AD mouse model, advocating the development of TNF-α-specific agents to subvert AD.

Original languageEnglish (US)
Pages (from-to)1768-1782
Number of pages15
JournalAmerican Journal of Pathology
Volume173
Issue number6
DOIs
StatePublished - Dec 2008

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

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. (2008). Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTg-AD mice. American Journal of Pathology, 173(6), 1768-1782. https://doi.org/10.2353/ajpath.2008.080528