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

• 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
• 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' s Disease; Alzheimer' 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

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-磷酸鞘氨醇(S1P)是一种生物活性分子，通过激活S1P受体(S1P1-5)来传递信号 调节全身免疫和炎症中的细胞过程。越来越多的证据表明，ab- S1P信号的异常与脑老化和阿尔茨海默病的病理生理相关 缓动(AD)。Fingolimod是一种用于治疗多发性硬化症(MS)的鞘氨醇类似物，通过 S1P1，以减少其对中枢神经系统的渗透，从而提供治疗疟疾的效果 随后的神经炎。Fingolimod跨越血脑屏障，新出现的证据表明 Fingolimod对中枢神经系统细胞的直接神经保护作用在AD的实验模型中出现了Fingolimod 减少β多肽的产生和神经毒性，促进小胶质细胞和 神经元。我们已经报道，在5xFAD小鼠中，AD的转基因模型，口服Fingolimod治疗减少 激活小胶质细胞和反应性星形胶质细胞，降低Aβ水平，增加海马神经细胞数量。 创世纪。我们的初步数据显示，在5xFAD小鼠中，Fingolimod的大部分神经保护作用发生在 低剂量，对神经炎性标志物有显著影响。我们假设老化会改变S1P信号- 大脑中的NALL系统，并驱动星形胶质细胞和小胶质细胞的促炎性激活，这是加速- 由于Aβ的积聚和使用S1P调制器的治疗将干扰这一过程并可能影响 年龄和阿尔茨海默病相关的神经病理和行为缺陷。为了检验这一假设，我们将使用两种不同的 以不同速率积累Aβ的AD转基因小鼠模型(5xFAD和PSAPP) 不同年龄的人大脑中会有大量的Aβ沉积。本研究包括三个目标。头两个目标是 AGE和AD样病理对野生型小鼠S1P系统影响的机制研究 以及在AD小鼠模型(AIM 1)中的作用，并确定S1P受体调节剂对神经肽的影响。 衰老和AD小鼠模型中的炎性反应及其对AD相关神经病理和认知功能的影响 模型(目标2)。后一项研究将包括通过在老鼠出现之前对其进行治疗来预防 AD样病理直到老年(1-18个月)，晚期疾病臂通过很好地治疗小鼠- 病理确诊(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激活，S1P系统，神经营养因子信号，如BDNF/TrkB，细胞因子，突触- 胶质细胞和凋亡标志物，以及由磁共振波谱(MRS)确定的小分子 反映神经代谢、兴奋毒性、氧化和渗透应激，以及膜的完整性。机器 将使用学习工具来整合这些数据集。第三个目标将是 S1P调节对衰老和阿尔茨海默病神经元和神经胶质功能指标影响的研究 使用非侵入性技术的小鼠模型，包括体内磁共振成像和 光谱学(MRI/MRS)和正电子发射断层扫描。