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: 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
• 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' 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; 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

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/文摘

项目成果

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

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

• DOI: 10.1002/advs.202206938
• 发表时间: 2023-07
• 期刊: Advanced science (Weinheim, Baden-Wurttemberg, Germany)

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.

• DOI: 10.1007/s00223-023-01100-4
• 发表时间: 2023-07
• 期刊: Calcified tissue international
• 影响因子: 4.2