TY - JOUR
T1 - Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTg-AD mice
AU - Janelsins, Michelle C.
AU - Mastrangelo, Michael A.
AU - Park, Keigan M.
AU - Sudol, Kelly L.
AU - Narrow, Wade C.
AU - Oddo, Salvatore
AU - LaFerla, Frank M.
AU - Callahan, Linda M.
AU - Federoff, Howard J.
AU - Bowers, William J.
PY - 2008/12
Y1 - 2008/12
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.
AB - 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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U2 - 10.2353/ajpath.2008.080528
DO - 10.2353/ajpath.2008.080528
M3 - Article
C2 - 18974297
AN - SCOPUS:57149101898
SN - 0002-9440
VL - 173
SP - 1768
EP - 1782
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -