Role of Cellular Senescence in the Bone-Brain Interplay

项目摘要/摘要 阿尔茨海默病(AD)是痴呆症最常见的形式，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 神经系统与年龄无关。然而，骨-脑相互作用的机制联系一直是 在很大程度上被忽视和研究不足。我们最近发现，相对于年轻的小鼠，老年小鼠的体重减少了 海马区血管密度和血脑屏障(BBB)完整性，以及我们的初步 数据表明，骨髓/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改变。特别是，我们在骨骼/骨骼中检测到积累的衰老细胞 老年小鼠(对年轻小鼠)和AD小鼠(对野生型小鼠)的骨髓。这些衰老的细胞主要是 骨/骨髓单核破骨前细胞(Pre-OCS)，获得一个独特的SASP，以PDGF-BB为 表达水平最高的因子。重要的是，老年动物的血清PDGF-BB水平显著升高(与 幼年动物)和AD小鼠(与对照组小鼠相比)，以及消融前OCS降低血清PDGF-BB 集中精神。我们的结果表明，骨/骨髓中的前OCS是血液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则维持脑内的动态平衡 血管系统在生理条件下，PDGF-BB浓度异常高可能导致脑部 血管损伤。事实上，我们发现消融OCS前病变会减弱与年龄相关的脑血管。 令人沮丧。我们的中心假设是，骨骼/骨髓中衰老的前OCS分泌过多的PDGF- BB进入血液循环，导致脑血管损伤，加速脑老化和AD进展。 在目标1中，我们将利用骨骼来确定SnBCs在正常脑老化和AD进展中的作用 骨髓移植方法和遗传小鼠诱导OCS前消融。我们将研究以下变化 衰老和阿尔茨海默病进展中的大脑病理和认知缺陷。在目标2中，我们将确定 系统性应用PDGF-BB促进SnBC分泌PDGF-BB参与脑老化和AD进展 中和抗体(Ab)，并利用遗传小鼠敲除或敲入前OCS中的PDGF-BB。我们会 观察衰老和AD进展过程中脑部病理和认知功能障碍的变化。正性 本研究的发现将对脑与骨在发育过程中的关系有新的认识 对于神经退行性疾病的研究，为AD的早期治疗提供了一条非常规但很有希望的途径。

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.