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Modeling Sympathetic Hyperactivity in Alzheimer’s Related Bone Loss
Journal of Alzheimer’s Disease ( IF 4 ) Pub Date : 2021-09-22 , DOI: 10.3233/jad-215007
Robert A Culibrk 1 , Ahmad S Arabiyat 1 , Carisa A DeKalb 1 , Mariah S Hahn 1
Affiliation  

Background:A significant subset of patients with Alzheimer’s disease (AD) exhibit low bone mineral density and are therefore more fracture-prone, relative to their similarly aged neurotypical counterparts. In addition to chronic immune hyperactivity, behavioral dysregulation of effector peripheralsympathetic neurons—which densely innervate bone and potently modulate bone remodeling—is implicated in this pathological bone reformation. Objective:Thus, there exists a pressing need for a robust in vitro model which allows interrogation of the paracrine interactions between the putative mediators of AD-related osteopenia: sympathetic neurons (SNs) and mesenchymal stem cells (MSCs). Methods:Toward this end, activated SN-like PC12 cells and bone marrow derived MSCs were cultured in poly(ethylene glycol) diacrylate (PEGDA) hydrogels in the presence or absence of the AD-relevant inflammatory cytokine tumor necrosis factor alpha (TNF-α) under mono- and co-culture conditions. Results:PC12s and MSCs exposed separately to TNF-α displayed increased expression of pro-inflammatory mediators and decreased osteopontin (OPN), respectively. These data indicate that TNF-α was capable of inducing a dysregulated state in both cell types consistent with AD. Co-culture of TNF-α-activated PC12s and MSCs further exacerbated pathological behaviors in both cell types. Specifically, PC12s displayed increased secretion of interleukin 6 relative to TNF-α stimulated monoculture controls. Similarly, MSCs demonstrated a further reduction in osteogenic capacity relative to TNF-α stimulated monoculture controls, as illustrated by a significant decrease in OPN and collagen type I alpha I chain. Conclusion:Taken together, these data may indicate that dysregulated sympathetic activity may contribute to AD-related bone loss.

中文翻译:

模拟阿尔茨海默病相关骨质流失中的交感神经过度活跃

背景:阿尔茨海默病 (AD) 患者的一个重要子集表现出低骨矿物质密度,因此相对于年龄相仿的神经典型患者更容易骨折。除了慢性免疫亢进之外,效应器外周交感神经元的行为失调(密集地支配骨骼并有效调节骨重塑)也与这种病理性骨重建有关。目的:因此,迫切需要一个强大的体外模型,该模型可以研究 AD 相关骨质减少的假定介质:交感神经元 (SN) 和间充质干细胞 (MSC) 之间的旁分泌相互作用。方法:为此,在存在或不存在 AD 相关炎症细胞因子肿瘤坏死因子 α (TNF-α) 的情况下,在聚乙二醇二丙烯酸酯 (PEGDA) 水凝胶中培养活化的 SN 样 PC12 细胞和骨髓来源的 MSC。 )在单一和共培养条件下。结果:分别暴露于 TNF-α 的 PC12 和 MSC 分别表现出促炎介质表达增加和骨桥蛋白 (OPN) 表达减少。这些数据表明 TNF-α 能够在两种细胞类型中诱导与 AD 一致的失调状态。TNF-α 激活的 PC12 和 MSC 的共培养进一步加剧了两种细胞类型的病理行为。具体而言,与 TNF-α 刺激的单一培养对照相比,PC12 显示白细胞介素 6 的分泌增加。同样,与 TNF-α 刺激的单一培养对照相比,MSC 的成骨能力进一步降低,如 OPN 和 I 型胶原 α I 链显着减少所示。结论:总而言之,这些数据可能表明交感神经活动失调可能导致 AD 相关的骨质流失。
更新日期:2021-09-24
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