Novel roles of TNF death receptor in amyloidosis in vivo

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DESCRIPTION (provided by applicant): Tumor necrosis factor type I receptor (TNFRI), a death receptor, mediates apoptosis and plays a crucial role in the interaction between the nervous and immune systems. A direct link between death receptor activation and signal cascade-mediated neuron death in brains with neurodegenerative disorders remains inconclusive. We have recently demonstrated that amyloid-beta protein (Abeta) a major component of plaques in the Alzheimer's diseased (AD) brain, induces neuronal apoptosis and this was mediated via alteration of apoptotic protease-activating factor (Apaf-1) expression that in turn induced activation of NF-KB. Abeta-induced neuronal apoptosis was reduced with lower Apaf-1 expression and little NF-KB activation was found in the neurons with mutated Apaf-1 or a deletion of TNFRI compared to the cells from wild type (WT) mice, suggesting that the TNF death receptor cascade is required for Abeta induced neuron death in vitro. To expand and further study the mechanisms in vivo, we propose that genetic inhibition of the TNF death receptor in APP mice may reduce AD-like pathology and ultimately prevent neuronal loss.