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

1-磷酸鞘氨醇诱导衰老和阿尔茨海默病炎症的调节

基本信息

批准号：
9403429
负责人：
ALPASLAN DEDEOGLU
金额：
$ 283.08万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9403429
关键词：
Affect Age Aging Agonist Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Amyloidosis Apoptotic Astrocytes Behavior Behavioral Blood - brain barrier anatomy Blood Circulation Brain Brain-Derived Neurotrophic Factor Cell physiology Cells Clinical Cognitive Data Data Set Deposition Development Disease Dose Drug usage Elderly Enzyme-Linked Immunosorbent Assay Etiology Experimental Models Family Caregiver Female Functional disorder GDNF gene Hippocampus (Brain)Immunity In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Learning Left Lymphocyte Machine Learning Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Measures Mediating Membrane Memory Metabolism Microglia Modeling Mus Neuraxis Neurodegenerative Disorders Neurons Normalcy Oral Outcome Measure Pathogenesis Pathology Peptides Performance Pharmacology Phenotype Population Positron-Emission Tomography Prevention Process Production Psyche structure Public Health Relapsing-Remitting Multiple Sclerosis Reporting Risk Factors Signal Pathway Signal Transduction Signaling Molecule Sphingolipids Sphingosine Sphingosine-1-Phosphate Receptor Stem cells Stress Synapses System Techniques Testing Therapeutic Therapeutic Effect Transgenic Mice Visuospatial Water Western Blotting Wild Type Mouse advanced disease age effect age related aging brain analog arm base cell type cognitive function cognitive testing conditioned fear cytokine design early onset edg-1 Protein excitotoxicity glial cell-line derived neurotrophic factor in vivo magnetic resonance spectroscopy indexing male morris water maze mouse model multiple sclerosis treatment neurochemistry neurogenesis neuroinflammation neuropathology neuroprotection neurotoxicity neurotrophic factor neurotropin normal aging oligodendrocyte progenitor prevent receptor relating to nervous system remyelination response small molecule spectroscopic imaging sphingosine 1-phosphate sphingosine kinase sphingosine-1-phosphate lyase sphingosine-1-phosphate phosphatase targeted agent therapeutic target tool transgenic model of alzheimer disease treatment effect

项目摘要

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.

1-磷酸盐（S1P）是一种生物活性分子，通过激活S1P受体（S1P1-5）发出信号调节全身免疫和炎症中的细胞过程。积累证据表明 - S1P信号传导的正常才与大脑衰老以及阿尔茨海默氏病的病理生理有关轻松（AD）。 Fingolimod是一种用于处理多发性硬化症（MS）的鞘氨醇类似物淋巴细胞中的S1P1以减少中枢神经系统的浸润，从而提供针对的治疗作用随后的神经炎症。 Fingolimod越过血脑屏障，并有新兴的证据表明 FingerLimod对CNS细胞的直接神经保护作用。在Ad Fingerlimod的实验模型中出现降低Aβ胡椒的产生和神经毒性，并促进小胶质细胞的神经保护神经元。我们报道说，在5xFAD小鼠（AD的转基因模型）中，口服Figolimod治疗下降小胶质细胞和反应性星形胶质细胞的激活，降低Aβ水平，并增加海马神经 - 创世纪。我们的初步数据表明，发生了5xFAD小鼠Fingerlimod的大多数神经保护作用低剂量，对神经炎症标记有重大影响。我们假设衰老改变了S1P sig- 大脑中的naling系统，并驱动星形胶质细胞和小胶质细胞的促炎性激活。 Aβ的积累和S1P调节剂的处理将干扰这一过程，并可能影响年龄和广告相关的神经病理学和行为缺陷。为了检验这个假设，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，因此相似 Aβ的量在不同年龄的大脑中沉积在大脑中。该研究包括3个目标。前两个目标是机械研究以确定年龄和类似AD样病理对野生型小鼠S1P系统的影响在AD的小鼠模型（AIM 1）中，并确定S1P受体调节剂对神经素的影响衰老和AD小鼠模型以及与广告相关的神经病理学和认知功能的施用模型（AIM 2）。后者的研究将包括在出现之前治疗小鼠的预防臂直到老年（1-18个月）的广告状病理学，并通过用良好的治疗小鼠治疗小鼠已建立的病理（15-18个月）。结果指标将包括认知行为，淀粉样变性，ac- 星形胶质细胞和小胶质细胞，S1P系统，神经营养蛋白信号传导的滋润，例如BDNF/TRKB，细胞因子，突触 - 神经胶质和凋亡标记，以及由磁共振光谱（MRS）确定的小分子反映神经代谢，兴奋性毒性，氧化和渗透应激以及膜完整性。机器学习工具将被雇用以整合这些数据集。第三个目标是转化部门研究确定S1P调制对衰老和AD中神经元和神经胶质功能指标指标的影响使用无创技术的小鼠模型，包括体内磁共振光谱成像和光谱法（MRI/MRS）和正电子发射断层扫描。