Role of Cellular Senescence in the Bone-Brain Interplay

细胞衰老在骨脑相互作用中的作用

• 批准号: 10417206
• 负责人: Mei Wan
• 金额: $ 40.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10417206
• 关键词: Ablation; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Animals; Attenuated; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Bone Density; Bone Diseases; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Brain; Brain Pathology; Cell Aging; Cells; Cerebrovascular Disorders; Cerebrovascular system; Clinical; Cognitive; Cognitive deficits; Cues; Data; Dementia; Development; Diagnostic; Diffuse; Disease; Disease Progression; Early treatment; Elderly; Endothelial Cells; Endothelium; Functional disorder; Genetic; Goals; Growth Factor; Health; Hippocampus (Brain); Homeostasis; Human; Impairment; In Situ; Incidence; Knock-in; Knock-in Mouse; Knock-out; Knockout Mice; Lead; Link; Modeling; Mononuclear; Mouse Strains; Mus; Neuraxis; Neurodegenerative Disorders; Organ; Osteoclasts; Osteoporosis; Pathologic; Patients; Pericytes; Permeability; Phenotype; Physiological; Population; Positioning Attribute; Rattus; Reporter; Role; Senile Plaques; Serum; Signal Transduction; Sorting - Cell Movement; Source; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Wild Type Mouse; Work; age related; aging brain; base; bone; bone loss; brain dysfunction; cell motility; cerebrovascular; comorbidity; cytokine; dementia risk; density; juvenile animal; neuropathology; neutralizing antibody; novel strategies; platelet-derived growth factor BB; promoter; public health relevance; receptor internalization; senescence; skeletal

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD), the most common form of dementia, is closely associated with osteoporosis, another age-associated bone disorder. It has been proposed that there is an interplay between skeletal and central nervous system independent of age. However, the mechanistic link for the bone-brain interaction has been largely overlooked and understudied. We recently found that old mice, relative to young mice, have reduced blood vessel density and compromised blood-brain barrier (BBB) integrity in hippocampus, and our preliminary data suggests that bone/bone marrow cells secreted cytokines/growth factors, which may contribute to these age-associated brain vascular changes. Particularly, we detected accumulated senescent cells in bone/bone marrow of old mice (vs. young mice) and AD mice (vs. wild-type mice). These senescent cells are primarily bone/bone marrow mononuclear pre-osteoclasts (Pre-OCs), which acquire a unique SASP, with PDGF-BB as the highest expressed factor. Importantly, serum PDGF-BB levels were markedly elevated in old animals (vs. young animals) and AD mice (vs. control mice), and ablation of the Pre-OCs reduced serum PDGF-BB concentration. Our results suggest that Pre-OCs in bone/bone marrow is a main source of elevated circulating PDGF-BB during aging and AD progression. While PDGF-BB maintains the homeostasis of the cerebral vasculature under physiological conditions, abnormally high concentration of PDGF-BB may lead to brain vascular impairment. Indeed, we found that ablation of Pre-OCs attenuated age-associated cerebral vascular impair. Our central hypothesis is that the senescent Pre-OCs in bone/bone marrow secrete excessive PDGF- BB into blood circulation, leading to cerebral vascular impairment to accelerate brain aging and AD progression. In Aim 1, we will determine the contribution of SnBCs to normal brain aging and AD progression using bone marrow transplantation approach and genetic mice to induce Pre-OCs ablation. We will examine the changes of brain pathologies and cognitive deficits during aging and AD progression. In Aim 2, we will determine the role of PDGF-BB secreted by SnBCs in brain aging and AD progression by systemically administering a PDGF-BB neutralizing antibody (Ab) and employing genetic mice to knock-out or knock-in PDGF-BB in Pre-OCs. We will examine the changes of brain pathologies and cognitive deficits during aging and AD progression. Positive findings in this study will provide new understanding on relationship between brain and bone in the development of neurodegenerative disease and present an unconventional but promising path for early treatment of AD.

项目总结/摘要 阿尔茨海默病（AD）是最常见的痴呆形式，与骨质疏松症密切相关， 与年龄相关的骨骼疾病有人提出，骨骼和中枢神经系统之间存在相互作用， 神经系统与年龄无关。然而，骨-脑相互作用的机制联系一直是 大部分被忽视和研究不足。我们最近发现，老年小鼠，相对于年轻小鼠， 血管密度和受损的血脑屏障（BBB）的完整性，我们的初步研究表明， 数据表明，骨/骨髓细胞分泌细胞因子/生长因子，这可能有助于这些 与年龄相关的脑血管变化。特别地，我们检测到骨/骨中积累的衰老细胞， 老年小鼠（与年轻小鼠）和AD小鼠（与野生型小鼠）的骨髓。这些衰老细胞主要是 骨/骨髓单核前破骨细胞（Pre-OC），其获得独特的SASP，PDGF-BB作为 最高的表达因素。重要的是，血清PDGF-BB水平在老年动物中显著升高（与对照组相比）。 年轻的动物）和AD小鼠（与对照小鼠相比），并且去除前OC降低了血清PDGF-BB 浓度.我们的结果表明，骨骼/骨髓中的前OC是循环升高的主要来源 PDGF-BB在衰老和AD进展中的作用而PDGF-BB维持脑组织的稳态， 在生理条件下，PDGF-BB的异常高浓度可能导致脑血管疾病。 血管损伤事实上，我们发现，消融前OC可以减少年龄相关的脑血管病变， 损害。我们的中心假设是，骨/骨髓中衰老的Pre-OC分泌过量的PDGF， BB进入血液循环，导致脑血管受损，加速大脑衰老和AD进展。 在目标1中，我们将使用骨密度测定来确定SnBCs对正常脑老化和AD进展的贡献。 骨髓移植方法和遗传小鼠诱导前OC消融。我们将研究 衰老和AD进展期间的脑病理和认知缺陷。在目标2中，我们将确定 通过全身施用PDGF-BB，在脑老化和AD进展中由SnBC分泌的PDGF-BB 中和抗体（Ab）和使用遗传小鼠敲除或敲入Pre-OC中的PDGF-BB。我们将 研究衰老和AD进展过程中大脑病理和认知缺陷的变化。积极 本研究的发现将对脑与骨在发育过程中的关系提供新的认识 的神经退行性疾病，并提出了一个非传统的，但有前途的途径，早期治疗AD。