Inflammation in Alzheimer’s disease : implicating tumor necrosis factor-alpha as a key mediator of disease pathogenesis

Thesis (Ph. D.)--University of Rochester. School of Medicine and Dentistry. Dept. of Microbiology and Immunology, 2008.Alzheimer’s disease (AD) is a complex neurodegenerative disorder that progressively impairs intellectual and emotional functioning in afflicted individuals. The disease is characterized pathologically by a temporal and spatial advancement of amyloid-beta (Aβ) deposition, neurofibrillary tangle formation, synaptic degeneration, and neuronal loss. Inflammatory processes have been implicated in initiating and/or propagating AD-associated pathology within the brain, as inflammatory cytokine expression and other markers of inflammation are pronounced in individuals with AD pathology. We utilized the 3xTg-AD mouse model (which harbors pathological features similar to human AD) to first identify inflammatory molecule(s) present in the brain prior to overt classical pathologies. We observed a significant 14.8-fold and 10.8-fold up-regulation in transcript levels of the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-α), and chemokine, monocyte chemoattractant protein-1 (MCP-1), respectively, specifically within the entorhinal cortex of these mice but not age-matched controls. Interestingly, correlative increases in numbers of F4/80-positive microglia/macrophage cells were regionally enhanced with respect to TNF-α and MCP-1 expression within the entorhinal cortex. Both microglia and neurons were found to express TNF-α transcripts. To further define the role of neuronally derived TNF-α in early AD pathogenesis, a recombinant adeno-associated virus (rAAV) vector expressing TNF-α was constructed and stereotactically delivered to “pre-pathologic” 3xTg-AD mice and non-transgenic (Non-Tg) control mice. Neuronal over-expression of TNF-α for 4 months hastened intracellular Aβ accumulation in 3xTg-AD mice with concomitant enhancement in microglial staining intensities. Following chronic neuronal expression of TNF-α in 3xTg-AD and Non-Tg mice for 10 months, significant transcriptional enhancement of TNF receptor II (TNFRII) and Jun-related genes with coincident neuronal death specifically within the brains of 3xTg-AD mice was observed. This indicates that chronic TNF-α expression alone is insufficiently neurotoxic, but that a pathologic interaction exists between TNF-α and the AD-related transgene products expressed by neurons in the 3xTg-AD mouse brain. These studies provide in vivo evidence for chronic neuronal TNF-α expression as a key mediator in perpetuating AD-related inflammatory events, and ultimately, neuronal death