With age neurons are at increasing risk for damage and degeneration. To a large part this is due to the pro-degenerative conditions that develop and have the capacity to initiate damage, necrosis or apoptosis. Many of these conditions build up and exist at sub-lethal levels for periods of time, ranging from days to years. There is much less information on how neurons cause cell loss via necrosis, apoptosis or related mechanisms. There is much less information on how neurons respond to sub-lethal levels of pro-apoptotic inducers. While several factors increase with age and can cause degeneration, tumor necrosis factor (TNF) and amyloid peptide (Abeta) have been implicated in neuronal degeneration and are candidate risk factors for studying the possible effects of sub-lethal pro-apoptotic insults on neurons. In this proposal, we test the hypothesis that TNF and/or Abeta impair neuronal function at concentrations that do not cause overt cell death (sub-lethal levels) by diminishing signal transduction mechanisms induced by growth-and neurotrophic factors, concentrating on effects on BDNF-activated TrkB signal transduction. Recently, TNF has been shown to impair in cortical neurons signal transduction of IGF-1 and phosphatidylinositol 3-kinase (PI 3-K), thereby increasing the risk for neurodegeneration. TrkB also operates via PI 3-K and related pathways. We test the hypothesis that TNF/Abeta interferes with the ability of BDNF to activate TrkB-mediated signal transduction, including the PI 3-K pathway (Aims 1 and 2). This may reduce neuronal survival capacity (Aim 3). We further hypothesize that these insults at sub-lethal levels, reduce critical gene transcription and the regulation of key effectors of brain plasticity. Specifically we hypothesize that these insults may interfere with the ability of BDNF to regulate CREB (Aim 4) and the expression of BDNF (Aim 5). As a result of impaired BDNF-TrkB signaling and BDNF production we hypothesize that the BDNF stimulation of select synaptic proteins will be reduced as will the maintenance and outgrowth of neurites (Aim 6). Together, these experiments may provide support for a mechanism (s) accounting for some of the well-known changes in brain aging and AD, including reduced activity dependent plasticity, synaptic integrity and neuronal survival.
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