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.

项目概要/摘要阿尔茨海默病 (AD) 是最常见的痴呆症，与骨质疏松症密切相关，而骨质疏松症是另一种痴呆症。与年龄相关的骨病。有人提出，骨骼和中枢之间存在相互作用。神经系统与年龄无关。然而，骨-脑相互作用的机制联系已被证实。很大程度上被忽视和研究不足。我们最近发现，老年小鼠相对于年轻小鼠，减少了海马体中的血管密度和受损的血脑屏障 (BBB) 完整性，以及我们的初步研究数据表明，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。特别是，我们检测到骨/骨中积累的衰老细胞年老小鼠（与年轻小鼠相比）和 AD 小鼠（与野生型小鼠相比）的骨髓。这些衰老细胞主要是骨/骨髓单核前破骨细胞 (Pre-OCs)，获得独特的 SASP，以 PDGF-BB 作为最高表达因子。重要的是，老年动物的血清 PDGF-BB 水平显着升高（与成年动物相比）。年轻动物）和 AD 小鼠（与对照小鼠相比），并且 Pre-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。 PDGF-BB 在衰老和 AD 进展过程中。 PDGF-BB维持大脑的稳态生理条件下的脉管系统，异常高浓度的PDGF-BB可能会导致脑血管损伤。事实上，我们发现 Pre-OCs 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/骨髓中衰老的 Pre-OCs 分泌过多的 PDGF- BB进入血液循环，导致脑血管受损，加速大脑老化和AD进展。在目标 1 中，我们将利用骨骼确定 SnBC 对正常大脑衰老和 AD 进展的贡献骨髓移植方法和基因小鼠诱导 Pre-OCs 消融。我们将检查以下变化衰老和 AD 进展过程中的大脑病理和认知缺陷。在目标 2 中，我们将确定以下角色：通过系统性施用 PDGF-BB，SnBC 分泌的 PDGF-BB 在大脑衰老和 AD 进展中发挥作用中和抗体（Ab）并使用基因小鼠敲除或敲入 Pre-OC 中的 PDGF-BB。我们将检查衰老和 AD 进展过程中大脑病理和认知缺陷的变化。积极的这项研究的结果将为大脑和骨骼在发育过程中的关系提供新的认识神经退行性疾病的研究，为 AD 的早期治疗提供了一种非常规但有前景的途径。

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

"Bone-SASP" in Skeletal Aging.