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

方案二：AB和IL-1B抑制BDNF信号转导及突触可塑性调节 炎症是与衰老和阿尔茨海默氏症等神经退行性疾病相关的常见机制 阿尔茨海默病(AD)、帕金森氏病(PD)、艾滋病痴呆和自身免疫性疾病。促炎细胞因子 如IL-1(3在大脑中升高，并与认知能力下降的风险增加和 神经退行性变。此外，在AD和AD/PD中，(3-淀粉样蛋白(A|3))积聚并与各种 可汇聚为神经元变性的病理性级联反应。虽然人们通常认为 这些因素导致大脑功能障碍的机制是神经元变性，这可能不是唯一或 最早的机制。我们认为A|3和IL-1|3的慢性升高干扰了神经功能 通过诱导一种在许多方面类似于胰岛素/IGF-1抵抗的“神经营养因子抵抗”状态。 具体地说，A(3)和IL-1(3)干扰神经营养因子BDNF诱导的信号转导，结果 在受损的信号中，神经元的脆弱性增加，并干扰活动依赖的可塑性，如 长时程增强。我们提出了三个目标。首先，我们将确定IL-1对TrkB的损伤 调节存在于停靠蛋白IRS-1的水平，决定IL-1是否损害BDNF依赖 阿尔茨海默病突触小泡蛋白的诱导及IL-1对脑源性神经营养因子依赖性的影响 LTP。其次，我们将确定IL-1是否可以与A_1协同作用，并发挥相加或协同作用 减少TrkB信号转导。第三，我们将研究TrkB逆行信号。BDNF/TrkB信号转导 AT突触依赖于局部信号转导，也依赖于TrkB逆行运输到胞体。我们 将使用一种新型的微流控培养室，它允许选择性地分离轴突和流体 轴突微环境的隔离。利用这个小室，我们的初步数据显示TrkB逆行 APP Tg2576神经元中的信号受到影响。我们将跟进这一令人兴奋的线索，定义流程并 确定机制。总体而言，拟议的实验将评估新的可能的机制 神经营养因子抵抗，可能损害大脑功能和可塑性，并增加 转变为更高级的疾病状态。

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.