Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA.
Department of Anatomy & Neurobiology, Northeast Ohio Medical University, Rootstown, OH, USA.
Neurobiol Aging. 2018 Jul;67:148-158. doi: 10.1016/j.neurobiolaging.2018.03.021. Epub 2018 Mar 23.
Low bone mineral density (BMD) is a significant comorbidity in Alzheimer's disease (AD) and may reflect systemic regulatory pathway dysfunction. Low BMD has been identified in several AD mouse models selective for amyloid-β or tau pathology, but these deficits were attributed to diverse mechanisms. In this study, we identified common pathophysiological mechanisms accounting for bone loss and neurodegeneration in the htau mouse, a tauopathy model with an early low BMD phenotype. We investigated the Wnt/β-catenin pathway-a cellular signaling cascade linked to both bone loss and neuropathology. We showed that low BMD persisted in male htau mice aged from 6 to 14 months, remaining significantly lower than tau-null and C57BL/6J controls. Osteogenic gene expression in female and male htau mice was markedly reduced from controls, indicating impaired bone remodeling. In both the bone and brain, htau mice showed alterations in Wnt/β-catenin signaling genes suggestive of increased inhibition of this pathway. These findings implicate dysfunctional Wnt signaling as a potential target for addressing bone loss in AD.
骨矿物质密度（BMD）降低是阿尔茨海默病（AD）的一种重要合并症，可能反映了全身调节途径的功能障碍。在几种针对淀粉样蛋白-β或tau 病理学的 AD 小鼠模型中已经发现了低 BMD，但这些缺陷归因于不同的机制。在这项研究中，我们确定了导致 htau 小鼠（一种具有早期低 BMD 表型的 tau 病模型）骨丢失和神经退行性变的共同病理生理机制。我们研究了 Wnt/β-连环蛋白途径——一种与骨丢失和神经病理学相关的细胞信号级联。我们表明，雄性 htau 小鼠的低 BMD 持续存在，从 6 到 14 个月大时，其 BMD 仍明显低于 tau 缺失型和 C57BL/6J 对照组。雌性和雄性 htau 小鼠的成骨基因表达明显低于对照组，表明骨重塑受损。在骨骼和大脑中，htau 小鼠的 Wnt/β-连环蛋白信号基因发生改变，表明该途径的抑制作用增强。这些发现表明，Wnt 信号功能障碍可能是治疗 AD 中骨丢失的一个潜在靶点。
