Pericyte-neuronal crosstalk in health and Alzheimer's Disease

健康和阿尔茨海默病中的周细胞-神经元串扰

基本信息

批准号：
10551225
负责人：
Zhen Zhao
金额：
$ 41.25万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10551225
关键词：
3-Dimensional Ablation Adult Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid beta-Protein Animal Model Basement membrane Behavior Behavioral Blood - brain barrier anatomy Blood Vessels Blood flow Brain Cells Central Nervous System Diseases Coculture Techniques Communication Complex Data Defect Dementia Development Developmental Process Disease Endothelial Cells Event Exhibits Functional disorder Gene Expression Goals Growth Growth Factor Guidelines Health Hippocampus Histologic Human IGF2R gene Impairment In Vitro Injury Insulin Signaling Pathway Insulin-Like Growth Factor II Insulin-Like-Growth Factor I Receptor Investigation Knockout Mice Knowledge Learning Mediating Memory Memory impairment Metabolic Metabolic Diseases Modeling Molecular Mus Mutation Nervous System Neurodegenerative Disorders Neuronal Dysfunction Neurons Outcome PIK3CG gene Paracrine Communication Pathogenesis Pathologic Pathology Pathway interactions Peptides Pericytes Phosphotransferases Play Reproducibility Role Signal Pathway Signal Transduction Stroke System Testing Therapeutic Toxic effect Transgenic Model Vascular System amyloid pathology behavior test brain abnormalities brain dysfunction brain health cerebrovascular conditional knockout data mining genetic manipulation glycogen synthase kinase 3 beta hyperphosphorylated tau in vivo information processing insight mouse model nerve stem cell nervous system disorder neurodevelopment neurogenesis neuroinflammation neuron development neurotrophic factor neurovascular neurovascular unit novel novel therapeutics paracrine peptide hormone receptor-mediated signaling single-cell RNA sequencing synaptogenesis tau Proteins tau-1 three dimensional cell culture tissue oxygenation

项目摘要

SUMMARY Neuronal functions and brain connectivity require a highly coordinated neurovascular unit (NVU). Neurons and vascular cells are not just adjacently located; they communicate with each other vigorously via different signaling modules. Pericytes are vascular mural cells of the endothelium and vital integrators of NVU functions, including maintaining the blood-brain barrier (BBB) and vascular integrity, regulating blood flow and tissue oxygenation, modulating neuroinflammation and supporting neuronal health. Pericyte injury and loss occur commonly in CNS diseases including Alzheimer’s disease and dementia. Our current knowledge implicates a critical role of pericytes for neuronal functions, which calls for a thorough investigation of pericyte–neuronal communication for different neuronal functions in health and particularly in Alzheimer’s disease. Using new 3D co-culture systems and novel transgenic models, we found that pericytes can directly regulate neurogenesis and neuronal functions, which can be attributed to pericyte-derived insulin-like growth factor 2. IGF2 is a peptide hormone with multiple roles in regulating metabolic functions and developmental processes. Human with IGF2 mutation and mice lacking IGF2 exhibited strong growth defects with abnormal neural development. IGF2 is produced locally in the brain; however, the roles of brain IGF2 in neurogenesis and neuronal dysfunction in CNS diseases are poorly understood. Our preliminary studies additionally indicated that IGF2 mediates pericyte-neuronal communication by activating a noncanonical IGF2R-Gαi-PLC pathway to enhance neuronal functions, as well as stimulating a canonical PI3K/Akt pathway to promote neurogenesis or suppressing Tau-phosphorylation. Here, we propose to study the functional crosstalk between pericytes and neurons, and examine the influence of IGF2-mediated paracrine signaling on neurogenesis during development (AIM1), on neuronal maturation and functions in adult (AIM2), and on AD-like pathogenesis (AIM3). Follow the Rigor and Reproducibility guidelines, we plan to: i) explore pericyte–neuronal crosstalk using 3D co-culture systems; ii) pinpoint the receptor mediated signaling by manipulating gene expressions and key kinase activities; iii) to determine the role of pericyte-specific IGF2 on neurogenesis and neuronal functions in new pericyte ablation and Igf2 conditional knockout mouse models; iv) examine the role of IGF2- mediated pericyte–neuronal crosstalk during AD-like pathogenies in mice using complex behavioral tests and histological analysis. We hope to generate first evidence of functional pericyte-neuron crosstalk for brain function in health and diseases, and pinpoint the mechanism of this signaling at molecular level for IGF2-mediated pericyte-neuron crosstalk. The outcomes may provide new insights to the IGF system and neurovascular interaction in brain, and close an important gap between metabolic diseases and CNS neurodegenerative diseases such as AD.

概括神经元功能和大脑连通性需要高度协调的神经血管单元（NVU）。神经元和血管细胞不仅毗邻。他们通过不同的信号模块。周细胞是内皮的血管壁细胞和NVU功能的重要整合剂，包括维持血脑屏障（BBB）和血管完整性，调节血流和组织氧合，调节神经炎症和支持神经元健康。周细胞受伤和损失通常在包括阿尔茨海默氏病和痴呆在内的中枢神经系统疾病中。我们当前的知识实现了周细胞对神经元功能的关键作用，该功能需要对周细胞神经元进行彻底研究在健康方面，特别是阿尔茨海默氏病的不同神经元功能的交流。使用新的3D共培养系统和新型转基因模型，我们发现周细胞可以直接调节神经发生和神经元功能，可以归因于周细胞衍生的胰岛素样生长因子2。 IGF2是一种在调节代谢功能和发育过程中具有多重作用的肽骑马。具有IGF2突变的人，缺乏IGF2的小鼠暴露了强生长缺陷，中性异常发展。 IGF2在大脑中局部产生；但是，脑IGF2在神经发生和中枢神经系统疾病中的神经元功能障碍知之甚少。我们的初步研究还表明 IGF2通过激活非规范的IGF2R-Gα-PLC途径来介导周细胞神经元通信增强神经元功能，并刺激规范的PI3K/AKT途径来促进神经发生或抑制tau磷酸化。在这里，我们建议研究周细胞之间的功能串扰神经元，并检查IGF2介导的旁分泌信号传导对神经发生的影响开发（AIM1），成人的神经元成熟和功能（AIM2）以及广告样发病机理（AIM3）。遵循严格和可重复性指南，我们计划：i）探索周围神经元串扰使用3D共培养系统； ii）通过操纵基因表达来查明接收器介导的信号传导和关键的激酶活动； iii）确定周细胞特异性IGF2在神经发生和神经元中的作用在新的周细胞消融和IGF2条件敲除鼠标模型中的功能； iv）检查IGF2-的作用使用复杂的行为测试和组织学分析。我们希望能为健康和疾病，并查明该信号在分子水平上的机制相声。结果可能会为IGF系统和大脑中的神经血管相互作用提供新的见解，并缩小代谢疾病与CNS神经退行性疾病（如AD）之间的重要差距。