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

Research output: Contribution to journalArticle

124 Citations (Scopus)

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
Externally publishedYes

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Alzheimer Disease
Tumor Necrosis Factor-alpha
Neurons
Amyloid
Transgenic Mice
Pathology
Cytokines
Dependovirus
Messenger RNA
Tumor Necrosis Factor Receptors
Brain
Transgenes
Interleukin-1beta
Cell Death
Inflammation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTg-AD mice. / Janelsins, Michelle C.; Mastrangelo, Michael A.; Park, Keigan M.; Sudol, Kelly L.; Narrow, Wade C.; Oddo, Salvatore -; LaFerla, Frank M.; Callahan, Linda M.; Federoff, Howard J.; Bowers, William J.

In: American Journal of Pathology, Vol. 173, No. 6, 12.2008, p. 1768-1782.

Research output: Contribution to journalArticle

Janelsins, MC, Mastrangelo, MA, Park, KM, Sudol, KL, Narrow, WC, Oddo, S, LaFerla, FM, Callahan, LM, Federoff, HJ & Bowers, WJ 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, vol. 173, no. 6, pp. 1768-1782. https://doi.org/10.2353/ajpath.2008.080528
Janelsins, Michelle C. ; Mastrangelo, Michael A. ; Park, Keigan M. ; Sudol, Kelly L. ; Narrow, Wade C. ; Oddo, Salvatore - ; LaFerla, Frank M. ; Callahan, Linda M. ; Federoff, Howard J. ; Bowers, William J. / Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTg-AD mice. In: American Journal of Pathology. 2008 ; Vol. 173, No. 6. pp. 1768-1782.
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AU - Sudol, Kelly L.

AU - Narrow, Wade C.

AU - Oddo, Salvatore -

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N2 - 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.

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