Published online before print October 30, 2008

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(American Journal of Pathology. 2008;173:1768-1782.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080528

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^*|| and William J. Bowers^*||

From the Department of Microbiology and Immunology,^* the Center for Neural Development and Disease, and Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York; the Department of Neurobiology and Behavior, University of California-Irvine, Irvine, California; and the Departments of Pathology and Laboratory Medicine,^¶ and Neurology,|| University of Rochester Medical Center, Rochester, New York

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