| Alzheimer's disease (AD) is a progressive degenerative disorder characterized by severe memory loss and cognitive impairment that elaborates in a temporal and spatial manner. Neuropathological correlates include amyloid-beta (Abeta) deposition, neurofibrillary tangles, synaptic loss, and neuronal cell death. AD is the most common form of dementia and lacks truly disease ameliorating therapy. It is estimated that 5.4 million Americans are currently afflicted by AD and as the population ages, the incidence is estimated to increase dramatically. By 2050 it is projected that between 11 and 16 million Americans will be living with the disorder, making research in the diagnosis, treatment, and prevention of this devastating malady a matter of great national importance.;Neuroinflammation drives disease AD pathogenesis through the production of pro-inflammatory molecules and activated glia. Tumor Necrosis Factor-alpha, a pleotropic pro-inflammatory cytokine, is produced in excess and implicated in Abeta-induced inflammation and cognitive decline. While TNF-alpha has been well studied, its purported function remains elusive, and surprisingly, little is known about the cell type- and stage-specific roles of this signaling molecule in AD. These questions are becoming ever more important since a growing body of research has been devoted to preclinical and clinical testing of non-selective anti-TNF-alpha modulating drugs for the treatment of AD. Our goal was to dissect the role of TNF-alpha and its associated receptors to gain insight into the specific signaling requirements and outcomes of this highly multifunctional protein, as a better understanding of TNF-alpha in AD may facilitate the development of safe and efficacious anti-TNF-alpha therapeutic interventions.;To examine TNF-alpha signaling requirements, we generated triple transgenic AD (3xTg-AD) mice lacking both TNF-receptor 1 (TNF-RI) and 2 (TNF-RII), the cognate receptors of TNF-alpha. These mice exhibit enhanced amyloid and tau-related pathological features by the age of 15 months, in stark contrast to age-matched 3xTg-AD counterparts. Moreover, 3xTg-ADxTNF-RI/RII knock out-derived primary microglia reveal reduced Abeta phagocytic marker expression and phagocytosis activity, indicating that intact TNF-alpha receptor signaling is critical for microglial-mediated uptake of extracellular Abeta peptide pools. Our data suggest that non-selective inhibition of TNF-alpha for long periods of time (potentially upwards of 20 years or more), where patients might receive anti-TNF-alpha therapeutics from the onset of symptoms until death, could unintentionally enhance disease severity.;In light of our observation revealing that chronic global TNF-alpha inhibition worsens disease, we subsequently studied the effects of selective TNF signaling regulation in a cell- and stage-specific manner. In the second part of this thesis, we utilized adeno-associated viral (AAV)-vector delivered siRNAs to selectively knockdown neuronal TNF receptor signaling. We demonstrate divergent roles for neuronal TNF-RI and TNF-RII, where suppression of opposing TNF-RII leads to TNF-RI-mediated exacerbation of Abeta and tau pathology in aged 3xTg-AD mice. Interestingly, dampening TNF-RII or both TNF-RI and TNF-RII together leads to a stage-independent increase of Iba1-positive microglial staining implying that neuronal TNF-RII may act non-cell autonomously on the microglial cell population. These results reveal that TNF receptor signaling is complex and it is unlikely that all cells and both receptors will respond positively to broad anti-TNF-alpha treatments at various stages of disease. In aggregate, our data support the development of cell-, stage-, and/or receptor-specific anti-TNF-alpha therapeutics for AD. |
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