Targeting neuroinflammation in AD with novel CX3CR1 agonists

项目摘要 Fractalkine蛋白（FKN，CX3CL1）抑制小胶质细胞活化，导致减少 在许多神经系统疾病中，包括阿尔茨海默病（AD），神经退行性变。在AD中， 在死后皮质组织中观察到FKN减少。我们研究了FKN及其在 广泛的神经退行性变，我们已经证明了FKN在多个 神经退行性疾病模型。我们的研究表明，可溶性FKN的过度表达， （sFKN）降低Tg4510小鼠中的tau病理学。更重要的是，我们观察到sFKN显著降低 脑萎缩和神经元丢失。在帕金森病（PD）小鼠模型中， sFKN，而不是抗切割的不溶性突变体FKN，减少了疾病病理和神经元损失。积极 可溶性与膜结合FKN的活性表明，可溶性分子具有激活 受体，并实现神经保护作用。这些观察结果促使人们假设， 可以利用该途径作为治疗AD的治疗方法。 高通量筛选产生了一系列化学支架，这些支架是新型小分子激动剂 CX3CR1适合通过此次融资机会进行进一步优化。先导化合物很有效， 高选择性，并已显示减少LPS介导的小胶质细胞活化。在此，我们建议 开发适于用作化学探针的口服生物可利用的有效CX3CR1激动剂化合物。这 该活动利用了Sanford Burnham Prebys和USF Health的独特资源。化学工作将 改进目前的先导化合物，以提高效力和选择性，并增强化合物的药物样活性。 特性.这些努力得到了由细胞和生化测定组成的强大测试漏斗的支持 CX3CR1信号，以及适当的反屏幕。理化和药理 将优化化合物的性质，然后在啮齿动物中进行药代动力学研究。我们将测试 在AD动物模型中的靶点参与和疗效，其中我们将鉴定至少一种CX3CR1激动剂 在体内具有有效的功效。

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.