Sphingosine-1-phosphate induced modulation of inflammation in aging and Alzheimer's disease

鞘氨醇1-磷酸（S1 P）是一种生物活性分子，其通过激活S1 P受体（S1 P1 -5）而发出信号， 调节全身免疫和炎症的细胞过程。越来越多的证据表明，AB- S1 P信号传导的异常与脑老化和阿尔茨海默病的病理生理学有关。 易（AD）。芬戈莫德是一种用于治疗多发性硬化症（MS）的鞘氨醇类似物， S1 P1，以减少它们向CNS的浸润，从而提供针对 随后的神经炎症。芬戈莫德可以穿过血脑屏障，新的证据表明， 芬戈莫德对CNS细胞的直接神经保护作用。在AD的实验模型中， 减少Aβ肽的产生和神经毒性，促进小胶质细胞的神经保护， 神经元我们已经报道，在5xFAD小鼠（AD的转基因模型）中，口服芬戈莫德治疗降低了 小胶质细胞和反应性星形胶质细胞的活化，降低Aβ水平，增加海马神经元- 创世纪我们的初步数据表明，芬戈莫德在5xFAD小鼠中的大部分神经保护作用发生在 在低剂量下对神经炎症标志物有主要影响。我们假设衰老改变了S1 P信号， 大脑中的神经系统并驱动星形胶质细胞和小胶质细胞的促炎症激活，从而加速 Aβ的积累导致了这一过程，用S1 P调节剂治疗会干扰这一过程，并可能影响 年龄和AD相关的神经病理学和行为缺陷。为了验证这个假设，我们将使用两个不同的 AD的转基因小鼠模型（5xFAD和PSAPP）以不同的速率积累Aβ， 不同年龄段的Aβ沉积在大脑中。本研究包括三个目标。前两个目标是 确定年龄和AD样病理学对野生型小鼠S1 P系统影响的机制研究 以及在AD小鼠模型中的作用（目的1），并确定S1 P受体调节剂对神经蛋白的作用。 在衰老和AD小鼠模型中的炎症以及在这些模型中AD相关的神经病理学和认知功能 模型（目标2）。后一项研究将包括一个预防组，即在小鼠出现前对其进行治疗。 AD样病理直到老年（1-18个月），以及通过用良好的- 病理学确诊（15-18个月）。结果测量将包括认知行为、淀粉样变性、ac- 星形胶质细胞和小胶质细胞的活化，S1 P系统，神经营养因子信号传导，例如BDNF/TrkB，细胞因子，突触- 神经胶质和凋亡标记物，以及通过磁共振波谱（MRS）确定的小分子， 反映神经代谢、兴奋性毒性、氧化和渗透压以及膜完整性。机 将使用学习工具来整合这些数据集。第三个目标将是 确定S1 P调节对衰老和AD中神经元和神经胶质功能指数的影响的研究 使用包括体内磁共振光谱成像的非侵入性技术的小鼠模型， 磁共振波谱（MRI/MRS）和正电子发射断层扫描。

Sphingosine 1-phosphate (S1P) is a bioactive molecule that signals by activating S1P receptors (S1P1-5) to regulate cellular processes in systemic immunity and inflammation. Accumulating evidence indicates that ab- normalities of S1P signaling are associated with brain aging and with the pathophysiology of Alzheimer's dis- ease (AD). Fingolimod, a sphingosine analog used for the treatment of multiple sclerosis (MS), acts through S1P1 in lymphocytes to reduce their infiltration into the CNS and thereby provides therapeutic effects against subsequent neuroinflammation. Fingolimod crosses the blood brain barrier and emerging evidence suggests the direct neuroprotective effect of fingolimod on CNS cells. In experimental models of AD fingolimod appears to reduce the production and the neurotoxicity of Aβ peptide and promote neuroprotection of microglia and neurons. We have reported that in 5xFAD mice, a transgenic model of AD, oral fingolimod treatment decreases the activation of microglia and reactive astrocytes, decreases Aβ levels, and increases hippocampal neuro- genesis. Our preliminary data show that most of the neuroprotective effects of fingolimod in 5xFAD mice occur at a low dose with major effects on neuroinflammatory markers. We hypothesize that aging alters the S1P sig- naling system in the brain and drives the proinflammatory activation of astrocytes and microglia that is acceler- ated by the buildup of Aβ and that treatment with S1P modulators will interfere with this process and may affect age- and AD-related neuropathology and behavioral deficits. To test this hypothesis we will use two different transgenic mouse models of AD (5xFAD and PSAPP) that accumulate Aβ at different rates such that similar amounts of Aβ are deposited in the brain at different ages. The study includes 3 aims. The first two aims are mechanistic studies to determine the effect of age and AD-like pathology on the S1P system in wild type mice and in the mouse models of AD (aim 1) and to determine the effects of S1P receptor modulators on neuroin- flammation in aging and AD mouse models and on AD-related neuropathology and cognitive function in these models (aim 2). The latter studies will include a prevention arm by treating the mice before the emergence of AD-like pathology until old age (1-18 months), and an advanced disease arm by treating the mice with well- established pathology (15-18 months). The outcome measures will include cognitive behavior, amyloidosis, ac- tivation of astrocytes and microglia, S1P system, neurotrophin signaling, e.g. BDNF/TrkB, cytokines, synaptic- glial- and apoptotic markers, and small molecules determined by magnetic resonance spectroscopy (MRS) that reflect neural metabolism, excitotoxic, oxidative, and osmotic stress, as well as membrane integrity. Machine learning tools will be employed to integrate these data sets. The third aim will be the translational arm of the study to determine the effects of S1P modulation on indices of neuronal and glial function in aging and in AD mouse models using noninvasive techniques including in vivo magnetic resonance spectroscopy imaging and spectroscopy (MRI/MRS) and positron emission tomography.