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) 发出信号 调节系统免疫和炎症的细胞过程。 S1P 信号传导的正常性与大脑衰老和阿尔茨海默病的病理生理学有关。 芬戈莫德（Fingolimod）是一种用于治疗多发性硬化症（MS）的鞘氨醇类似物，通过 淋巴细胞中的 S1P1 可减少其对 CNS 的浸润，从而提供针对 随后的神经炎症。芬戈莫德穿过血脑屏障，新的证据表明。 芬戈莫德对中枢神经系统细胞的直接神经保护作用在 AD 实验模型中出现。 减少 Aβ 肽的产生和神经毒性，促进小胶质细胞和神经细胞的神经保护 我们已经报道，在 5xFAD 小鼠（AD 转基因模型）中，口服芬戈莫德治疗可减少神经元的活性。 小胶质细胞和反应性星形胶质细胞的激活，降低 Aβ 水平，并增加海马神经元 我们的初步数据表明，芬戈莫德的大部分神经保护作用发生在 5xFAD 小鼠中。 低剂量对神经炎症标志物有重大影响，我们发现衰老会改变 S1P 信号。 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激活，从而加速 由于 Aβ 的积累，S1P 调节剂治疗会干扰这一过程，并可能影响 为了检验这一假设，我们将使用两种不同的神经病理学和行为缺陷。 AD 转基因小鼠模型（5xFAD 和 PSAPP）以不同的速率积累 Aβ，因此类似 不同年龄阶段大脑中沉积的 Aβ 量有 3 个目标：前两个目标是。 确定年龄和 AD 样病理对野生型小鼠 S1P 系统影响的机制研究 并在 AD 小鼠模型中（目标 1）确定 S1P 受体调节剂对神经元的影响 衰老和 AD 小鼠模型中的炎症以及这些模型中与 AD 相关的神经病理学和认知功能 模型（目标 2）将包括通过在小鼠出现之前进行治疗来进行预防。 AD 样病理直到老年（1-18 个月），以及通过对小鼠进行良好治疗的晚期疾病组 确定的病理学（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、神经营养素信号传导，例如 BDNF/TrkB、细胞因子、突触 神经胶质细胞和细胞凋亡标记物以及通过磁共振波谱 (MRS) 测定的小分子 反映神经代谢、兴奋性毒性、氧化和渗透应激以及膜完整性。 第三个目标将是利用学习工具来整合这些数据集。 研究确定 S1P 调制对衰老和 AD 中神经和神经胶质功能指数的影响 使用非侵入性技术的小鼠模型，包括体内磁共振波谱成像和 光谱学 (MRI/MRS) 和正电子发射断层扫描。

项目成果

Fingolimod mitigates memory loss in a mouse model of Gulf War Illness amid decreasing the activation of microglia, protein kinase R, and NFκB.

Fingolimod 通过减少小胶质细胞、蛋白激酶 R 和 NFκB 的激活来减轻海湾战争疾病小鼠模型的记忆丧失。

• DOI: 10.1016/j.neuro.2023.05.006
• 发表时间: 2023-05-01
• 期刊: Neurotoxicology
• 影响因子: 3.4
• 作者: I. Carreras;Younghun Jung;Jonathan Lopez;C. Tognoni;A. Dedeoglu
• 通讯作者: A. Dedeoglu

Dual dose-dependent effects of fingolimod in a mouse model of Alzheimer's disease.

芬戈莫德在阿尔茨海默病小鼠模型中的双重剂量依赖性作用。

• 发表时间: 2019
• 影响因子: 4.6
• 作者: Carreras, Isabel;Aytan, Nurgul;Choi, Ji;Tognoni, Christina M;Kowall, Neil W;Jenkins, Bruce G;Dedeoglu, Alpaslan
• 通讯作者: Dedeoglu, Alpaslan

Dysregulation of sphingosine-1-phosphate (S1P) and S1P receptor 1 signaling in the 5xFAD mouse model of Alzheimer's disease.

阿尔茨海默病 5xFAD 小鼠模型中 1-磷酸鞘氨醇 (S1P) 和 S1P 受体 1 信号传导失调。

• 发表时间: 2023-01-15
• 影响因子: 2.9
• 作者: Jung, Younghun;Lopez;Tognoni, Christina M;Carreras, Isabel;Dedeoglu, Alpaslan
• 通讯作者: Dedeoglu, Alpaslan