Modeling Sympathetic Hyperactivity in Alzheimer’s Related Bone Resorption

A significant subset of Alzheimer’s Disease (AD) patients exhibit low bone mineral density and are therefore more fracture-prone relative to similarly aged neurotypical populations. In addition to chronic immune hyperactivity, behavioral dysregulation of effector peripheral sympathetic neurons (SNs) – which densely innervate bone tissue and potently regulate bone remodeling – has been implicated in this pathology. The current clinical “gold standard” for stimulating functional regeneration of damaged bone tissue involves the implementation of harvested autografts; however, positive outcomes are limited due to finite donor availability, donor site morbidity, complex grafting procedures, and high engraftment failure rates. Thus, there exists a pressing need for a robust in vitro model which can be applied toward generating novel tissue engineering treatment strategies – one which faithfully recapitulates the paracrine interactions observed between the predominant mediators of Alzheimer’s related osteopenia: SNs and mesenchymal stem cells (MSCs). Toward this end, we cocultured activated SN-like PC12s and human MSCs (hMSCs) in a poly(ethylene glycol) diacrylate (PEGDA) transwell architecture.The presence of SN-like PC12s and inflammatory culture conditions exerted differential effects on the osteo-regulatory profile of hMSCs. TNF- induced a significant decrease in angiogenic factor VEGF, and osteogenic factor BMP-2, in hMSCs irrespective of coculture with PC12s; however, the effects of PC12 coculture dominated in generating a decrease in COL1A1, the predominant structural protein in bone. Furthermore, the combined effects of PC12 coculture and TNF- stimulation engendered a nearly 10-fold reduction in OPN, a regulator of bone mineralization. These results support the hypothesis that activated SN-like PC12 cells indeed potently inhibit the osteogenesis of hMSCs.