Browsing by Subject "Nerve Degeneration"
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Item The Role of TNF Signaling In Regulating Beta-Amyloid Burden in the 3xtgad Mouse Model of Alzheimer's Disease(2008-05-13) McAlpine, Fiona E.; Tansey, MaluMicroglial activation and overproduction of inflammatory mediators in the CNS have been implicated in Alzheimer's Disease (AD), but the precise nature of the key molecular mediators of neurotoxicity that directly contribute to neurodegeneration or loss of specific neuronal populations is less clear. The pro-inflammatory cytokine Tumor Necrosis Factor (TNF) has been implicated in AD by its elevated presence in serum and post-mortem brains of patients with AD. To test the hypothesis that TNF-dependent neuroinflammation and neurotoxicity contributes to the increased microglial burden and exacerbated pathology observed in the hippocampus and cortex of 3xTgAD mice (transgenic mouse expressing human familial AD mutations in APP, PS1, and a familial frontotemporal dementia mutation in tau) after chronic systemic LPS exposure, we inhibited TNF signaling with novel engineered dominant negative TNF inhibitors (DN-TNF) selective for soluble TNF (solTNF) or lentiviral-derived DN-TNF to achieve long-term inhibition of TNF activity and halt or delay the early stages of amyloid-associated neuropathology. In vitro, cells infected with lenti-pro-DN-TNF-IRES-GFP produce sufficient levels of DN-TNF protein to block nuclear translocation of p65 in response to stimulation by TNF. Infection with lenti-DN-TNF also blocks solTNF-induced activation of primary microglia. Results from in vivo studies indicate that short-term pharmacological inhibition as well as long-term lentiviral-driven inhibition of soluble TNF signaling decreases the accumulation of intraneuronal full length APP in hippocampus and cortex induced by chronic systemic inflammation. To our knowledge, this is the first study that selectively inhibits soluble TNF signaling in an acute manner using a pharmacologic agent, thereby directly linking endogenous TNF activity in vivo to accumulation of APP in a model of Alzheimer's disease. Targeted inhibition of soluble TNF in the central nervous system may represent a new therapeutic approach to slow the appearance of amyloid pathology, cognitive deficits, and possibly the progressive loss of neurons in AD.Item Tumor Necrosis Factor Dependent Mechanisms and Neuroprotective Strategies in Models of Parkinson's Disease(2008-5-13) McCoy, Melissa Kay; Tansey, Mal󠇮Parkinson's disease is a chronic, progressive, neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra that innervate the striatum. Although the nigral cell loss that causes motor dysfunction in Parkinson's disease has been identified for some time, the mechanisms that lead to this dopaminergic neuron loss are unclear. Elevated levels of the cytokine tumor necrosis factor in cerebrospinal fluid and postmortem brains of Parkinson's patients and in animal models of the disease implicate tumor necrosis factor in contributing to disease pathology; but a specific role for this cytokine in mediating loss of dopaminergic neurons in Parkinson's disease has not been clearly established. Here I demonstrate that neutralization of soluble tumor necrosis factor in vivo with a recombinant dominant-negative tumor necrosis factor inhibitor reduced 6-hydroxydopamine-induced nigral degeneration by 50% and attenuated amphetamine-induced rotational behavior, indicative of striatal dopamine preservation in a rodent model of Parkinson's disease. Similar protective effects were observed with in vivo chronic co-infusion of dominant-negative tumor necrosis factor inhibitor with a proinflammatory initiator, low-dose lipopolysaccharide, into the substantia nigra of rodents, confirming a role for soluble tumor necrosis factor inhibitor-dependent neuroinflammation in contributing to nigral degeneration. In rat embryonic midbrain neuron/glia mixed cell cultures exposed to lipopolysaccharide, delayed administration of dominant-negative tumor necrosis factor inhibitor prevented degeneration of dopaminergic neurons despite sustained microglia activation. Addition of a dominant-negative tumor necrosis factor inhibitor also attenuated 6-hydroxydopamine-induced dopaminergic neuron toxicity in vitro. In this dissertation the ability of lentiviral-encoded dominant-negative tumor necrosis factor inhibitor to provide neuroprotection was also investigated. Intranigral delivery of lentiviral dominant-negative tumor necrosis factor inhibitor in a hemiparkinsonian rat 6-hydroxydopamine model attenuated nigral dopaminergic neuron loss and reduced behavior deficits when compared to control lentiviral-infected animals. Collectively, these data identify tumor necrosis factor signaling in contributing to dopaminergic neuron loss in vitro and in vivo in two chronic rat models of Parkinson's disease, and provide evidence that delaying the progressive degeneration of the nigrostriatal pathway in the early stages of Parkinson's disease in humans may be therapeutically feasible with agents that block soluble tumor necrosis factor signaling.Item UCHLI in the Mammalian Nervous System(2008-9-18) Myers, Kalisa Galina; Lin, WeichunUCHL1, or Ubiquitin Carboxy Terminal Hydrolase L1, is a de-ubiquitinating enzyme (DUB) thought to be involved in ubiquitin recycling. Beyond this, its natural function is almost wholly unknown. Mice lacking this enzyme exhibit a severe and rapidly progressing neurodegenerative phenotype. Using one of these mouse models, in which a lacz-neo construct is cloned in under the UCHL1 promoter, we have studied the gross progression of phenotype of these mice, characterized the expression pattern of UCHLO1 in brain, spinal cord, and lumbar dorsal root ganglia, described degeneration of muscle spindles, and established a timecourse of degeneration of neuromuscular junctions. Presented in this thesis is the culmination of these studies.