Role of Cellular Senescence in the Bone-Brain Interplay

细胞衰老在骨脑相互作用中的作用

基本信息

批准号：
10634546
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
项目类别：
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/10634546
关键词：
Ablation Acceleration Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos 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 Bone Resorption Brain Brain Pathology Cell Aging Cell Separation Cell secretion Cells Central Nervous System 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 Homeostasis Human Impairment In Situ Incidence Knock-in Knock-in Mouse Knock-out Link Modeling Mononuclear Mouse Strains Mus Neurodegenerative Disorders Organ Osteoclasts Osteoporosis Pathologic Patients Pericytes Permeability Phenotype Physiological Population Positioning Attribute Proliferating Rattus Reporter Role Senile Plaques Serum Signal Transduction Sorting Source Testing Tissues Transgenic Mice Transgenic Organisms Visualization Wild Type Mouse Work age related aging brain bone bone loss brain dysfunction cerebrovascular comorbidity cytokine dementia risk density juvenile animal migration neuropathology neutralizing antibody novel strategies platelet-derived growth factor BB promoter public health relevance receptor internalization risk prediction senescence skeletal

项目摘要

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.

项目摘要/摘要阿尔茨海默氏病（AD）是痴呆的最常见形式，与骨质疏松症密切相关，另一种与年龄相关的骨病。有人提出，骨骼和中央之间存在相互作用神经系统独立于年龄。但是，骨 - 脑相互作用的机械链接已经在很大程度上被忽视和研究了。我们最近发现，相对于年轻小鼠的老鼠已经减少了海马中的血管密度和受损的血脑屏障（BBB）完整性，我们的初步数据表明骨/骨髓细胞分泌细胞因子/生长因子，这可能会导致这些因素与年龄相关的脑血管变化。特别是，我们检测到骨/骨中累积的衰老细胞老鼠骨髓（与年轻小鼠）和AD小鼠（vs.野生型小鼠）。这些衰老细胞主要是骨/骨髓单核前细胞（前OC），以PDGF-BB为最高表达因素。重要的是，老动物的血清PDGF-BB水平明显升高（Vs。年轻动物）和AD小鼠（相对于对照小鼠），以及前OC的消融降低了血清PDGF-BB 专注。我们的结果表明，骨/骨髓中的前OC是循环升高的主要来源衰老和AD进展过程中的PDGF-BB。而PDGF-BB保持大脑的稳态脉管系统在生理条件下，异常高的PDGF-BB可能导致大脑血管障碍。确实，我们发现前OC的消融减弱了与年龄相关的脑血管妨害。我们的中心假设是骨/骨髓中的衰老前oc会分泌过多的PDGF- BB进入血液循环，导致脑血管损伤加速脑衰老和AD进展。在AIM 1中，我们将确定SNBC对正常脑衰老和AD进展的贡献骨髓移植方法和遗传小鼠诱导前oc的消融。我们将检查的变化衰老和AD进展过程中的脑病理和认知缺陷。在AIM 2中，我们将确定 SNBC在脑老化和AD进展中分泌的PDGF-BB通过系统地管理PDGF-BB 中和抗体（AB）和使用遗传小鼠在前OC中敲除或敲除PDGF-BB。我们将检查衰老和AD进展过程中脑病理和认知缺陷的变化。积极的这项研究中的发现将为发育中的大脑与骨骼之间的关系提供新的了解神经退行性疾病的疾病，并提出了非常规但有前途的AD治疗途径。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cellular senescence in musculoskeletal homeostasis, diseases, and regeneration.

DOI：
10.1038/s41413-021-00164-y
发表时间：
2021-09-10
期刊：
Bone research
影响因子：
12.7
作者：
Wan M;Gray-Gaillard EF;Elisseeff JH
通讯作者：
Elisseeff JH

Bone-derived PDGF-BB drives brain vascular calcification in male mice.

DOI：
10.1172/jci168447
发表时间：
2023-12-01
期刊：
JOURNAL OF CLINICAL INVESTIGATION
影响因子：
15.9
作者：
Wang, Jiekang;Fang, Ching-Lien;Noller, Kathleen;Wei, Zhiliang;Liu, Guanqiao;Shen, Ke;Song, Kangping;Cao, Xu;Wan, Mei
通讯作者：
Wan, Mei

Senescent preosteoclast secretome promotes metabolic syndrome associated osteoarthritis through cyclooxygenase 2.

DOI：
10.7554/elife.79773
发表时间：
2022-07-26
期刊：
ELIFE
影响因子：
7.7
作者：
Su, Weiping;Liu, Guanqiao;Mohajer, Bahram;Wang, Jiekang;Shen, Alena;Zhang, Weixin;Liu, Bin;Guermazi, Ali;Gao, Peisong;Cao, Xu;Demehri, Shadpour;Wan, Mei
通讯作者：
Wan, Mei

Elevated PDGF-BB from Bone Impairs Hippocampal Vasculature by Inducing PDGFRβ Shedding from Pericytes.