AB AND IL - 1B SUPPRESS BDNF SIGNALING AND THE REGULATION OF SYNAPTIC PLASTICITY

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Project 2: AB and IL-1B Suppress BDNF Signaling and the Regulation of Synaptic Plasticity Inflammation is a common mechanism associated with aging and neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), AIDS dementia, and autoimmune disease. Proinflammatory cytokines such as IL-1 (3 become elevated in the brain and are associated with an increased risk of cognitive decline and neurodegeneration. Further, in AD and AD/PD, (3-amyloid (A|3) accumulates and is linked to various pathological cascades that can converge on neuronal degeneration. While it is usually assumed that the mechanism by which these factors cause brain dysfunction is neuronal degeneration, this may not be the only or the earliest mechanism. We propose that a chronic elevation in A|3 and IL-1|3 interferes with neuronal function by inducing a state of "neurotrophic factor resistance" similar in many ways to insulin/IGF-1 resistance. Specifically, A(3 and IL-1 (3 interfere with signal transduction induced by the neurotrophic factor BDNF, resulting in impaired signaling, increased vulnerability of neurons and interference with activity dependent plasticity such as long term potentiation. We propose 3 Aims. First, we will determine if the impairment of IL-1 on TrkB regulation resides at the level of the docking protein IRS-1, determine if IL-1 impairs the BDNF dependent induction of synaptic vesicles proteins reduced in AD, and examine the effect of IL-1 on BDNF-dependent theta LTP. Second, we will then determine if IL-1 can act in concert with A_ and exert an additive or synergistic reduction on TrkB signal transduction. Third, we will examine TrkB retrograde signaling. BDNF/TrkB signaling at synapses depends on local signal transduction and also retrograde TrkB retrograde transport to the soma. We will use a novel microfluidic culture chamber, which allows the selective isolation of axons and the fluidic isolation of axonal microenvironment. Using this chamber, our preliminary data suggest retrograde TrkB signaling is compromised in APP Tg2576 neurons. We will follow up this exciting lead, define the process and determine the mechanisms. Overall, the proposed experiments will evaluate new possible mechanisms of neurotrophic factor resistance that may compromise brain function and plasticity and increase the risk for conversion to more advanced disease states.