Targeting neuroinflammation in AD with novel CX3CR1 agonists

项目总结 Fractalkine蛋白(FKN，CX3CL1)抑制小胶质细胞活化导致细胞数量减少 许多神经疾病中的神经变性，包括阿尔茨海默病(AD)。在公元一年，一个大的 在死后皮质组织中观察到FKN的减少。我们研究了FKN及其在 广泛的神经变性，我们已经证明了FKN在多发性硬化中的有益作用。 神经退行性疾病模型。我们的工作表明，FKN的一种可溶性形式的过度表达 (SFKN)可降低Tg4510小鼠的tau病理改变。更重要的是，我们观察到sFKN显著减少 这些小鼠的脑萎缩和神经元丢失。在帕金森病(PD)小鼠模型中，过度表达 SFKN，但不是抗切割的，不可溶的突变体FKN，可以减少疾病病理和神经元丢失。正性 可溶性FKN与膜结合的FKN的活性表明，可溶性分子具有激活的潜力 该受体具有神经保护作用。这些观察结果促使人们假设FKN 通路可作为治疗阿尔茨海默病的途径。 高通量筛选产生了一系列新型小分子激动剂的化学支架 CX3CR1适合通过此次融资机会进行进一步优化。先导化合物是有效的，而且 高选择性，并已被证明可减少内毒素介导的小胶质细胞的激活。在此，我们建议 开发口服生物利用型、有效的CX3CR1激动剂化合物，适合用作化学探针。这 Campaign利用了Sanford Burnham Prebys和USF Health的独特资源。化学方面的努力将 提炼目前的先导化合物以提高效力和选择性，并增强化合物的药物性质 属性。这些努力得到了强大的测试漏斗的支持，该测试漏斗由细胞和生化分析组成 CX3CR1信令，以及适当的计数器屏幕。理化和药理作用 这些化合物的性质将得到优化，随后将进行啮齿动物的药代动力学研究。我们将测试 在AD动物模型中，我们将识别至少一种CX3CR1激动剂的靶向参与和有效性 在体内有很强的药效。

PROJECT SUMMARY Fractalkine protein (FKN, CX3CL1) suppresses microglial activation leading to decreased neurodegeneration in a number of neurological disorders, including Alzheimer's disease (AD). In AD, a large reduction in FKN has been observed in postmortem cortical tissue. We have studied FKN and its role in neurodegeneration extensively, and we have demonstrated a beneficial effect of FKN in multiple neurodegenerative disease models. Our work demonstrates that overexpression of a soluble form of FKN (sFKN) decreases tau pathology in Tg4510 mice. More importantly, we observed that sFKN significantly reduces brain atrophy and neuron loss in these mice. In Parkinson's disease (PD) mouse models, overexpression of sFKN, but not a cleavage-resistant, insoluble mutant FKN, reduces disease pathology and neuron loss. Positive activity with soluble versus membrane-bound FKN suggests that a soluble molecule has the potential to activate the receptor and achieve neuroprotective effects. These observations prompted the hypothesis that the FKN pathway could be exploited as a therapeutic approach to treat AD. High-throughput screening produced a series of chemical scaffolds that are novel small molecule agonists of CX3CR1 suitable for further optimization through this funding opportunity. The lead compound is potent and highly selective, and has been shown to reduce LPS-mediated activation of microglia. Here, we propose to develop orally bioavailable potent CX3CR1 agonist compounds suitable for use as chemical probes. This campaign leverages the unique resources of Sanford Burnham Prebys and USF Health. Chemistry efforts will refine the current lead compound to improve potency and selectivity, and enhance the compound's drug-like properties. These efforts are supported by a robust testing funnel consisting of cellular and biochemical assays of CX3CR1 signaling, as well as appropriate counter-screens. The physicochemical and pharmacological properties of the compounds will be optimized, followed by pharmacokinetic studies in rodents. We will test for target engagement and efficacy in the AD animal models, in which we will identify at least one CX3CR1 agonist with potent efficacy in vivo.