Vitamin D and beta-amyloid signaling in hyperparathyroidism

摘要 维生素D缺乏在老年人中是一个普遍存在的问题，并会引发后遗症 对这一弱势群体尤其有害。甲状旁腺功能亢进症(HPT)通常与低 维生素D状态和钙稳态的破坏是这种疾病的主要特征，可能会导致 对老年人的一系列有害后果，包括骨密度下降，肌肉无力，以及 摔倒和病理性骨折的风险增加。作为负责荷尔蒙的主要内分泌器官 为了控制血清钙水平，甲状旁腺是维生素D作用的已知靶点，但 是我们对维生素D缺乏和维生素D受体(VDR)减弱的理解中的主要差距 信号转导与HPT的病因和临床表现有关。机械化的中间体连接着 HPT中VDR对甲状旁腺激素(PTH)的高分泌作用尚不清楚，目前VDR-PTH高分泌模型的研究进展尚不清楚。 甲状旁腺钙敏感受体(CaSR)的依赖性表达不能解释 甲状旁腺组织中CaSR丰度下调不是HPT的显著比例 观察到的。最近，我们小组的几个关键发现提出了一种可测试的维生素D介导的新模式 在甲状旁腺中的作用。首先，我们证明了GABA B1受体(GABAB1R)可以形成异二聚体 与CaSR络合物通过对抗CaSR与其专一性偶联促进PTH紧张性高分泌 下游G蛋白效应子GQ/11和Gi。其次，基于最近的一份报告表明，可溶的 我们发现，淀粉样前体蛋白(APP)的多肽衍生物可以结合并激活神经元中的GABAB1R APP衍生肽Aβ1-42可增加CASR中甲状旁腺组织的最大甲状旁腺激素分泌 GABAB1R依赖的方式。VDR表达和血清维生素D水平与 APP、Aβ1-42的相对丰度，Aγ1-42产生所需的β-和β-分泌酶，以及磷酸化的 微管相关蛋白Tau(Ptau)的形式。甲状旁腺APP的功能性消融 抑制VDR KO小鼠HPT的发生，Tau磷酸化抑制剂可阻断这种作用 Aβ1-42促进甲状旁腺素高分泌。这些数据表明，由VDR活性丧失驱动的HPT可能 至少部分是通过Aβ1-42和ptau的非调控表达而产生的。基于这些发现，我们 假设衰老诱导的甲状旁腺素1-42介导的信号增加驱动紧张性β高分泌，并且 维生素D缺乏通过缓解对Aβ1-42产生和释放的抑制而加剧甲状旁腺功能亢进症的严重性 Tau/ptau表达式。为了检验这个模型，我们提出了三个互补的、机械性的具体目标：(1) 阐明Aβ1-42在CaSR、GABAB1R和下游信号事件中的分子作用 甲状旁腺素高分泌；(2)确定阻断Aβ1-42和Tau的产生或活性是否延迟甲状旁腺素 建立CaSR不足的小鼠模型；以及(3)描述VDR与VDR之间的因果关系 甲状旁腺中的Aβ1-42/PTAU信号通路。通过定义CASR/GABAB1R/Aβ1-42的贡献 信号轴到甲状旁腺素高分泌，这项工作将提供一个更清晰的机制理解。 β-淀粉样多肽、维生素D状态和甲状旁腺功能之间的意外联系。

ABSTRACT Vitamin D deficiency is a widespread problem among the elderly and can precipitate sequelae that are particularly harmful to this vulnerable population. Hyperparathyroidism (HPT) is commonly associated with low vitamin D status, and the disruption in calcium homeostasis that is the cardinal feature of this disease can lead to a range of deleterious outcomes among the elderly, including loss of bone density, muscle weakness, and increased risk of falls and pathological fracture. As the primary endocrine organs responsible for hormonal control of serum calcium levels, the parathyroid glands are a known target for the actions of vitamin D, yet there are major gaps in our understanding of how vitamin D deficiency and attenuated vitamin D receptor (VDR) signaling contribute to the etiology and clinical presentation of HPT. The mechanistic intermediates linking the VDR to parathyroid hormone (PTH) hypersecretion in HPT remain unknown, and the current model of VDR- dependent expression of the calcium sensing receptor (CaSR) in the parathyroid does not account for the significant proportion of HPT cases where downregulation of CaSR abundance in parathyroid tissue is not observed. Recently, several key findings from our group suggest a testable new model for vitamin D-mediated actions in the parathyroid gland. First, we showed that the GABA B1 receptor (GABAB1R) can form heterodimeric complexes with CaSR, promoting tonic hypersecretion of PTH by opposing the coupling of CaSR with its obligate downstream G-protein effectors Gq/11 and Gi. Second, building upon a recent report demonstrating that soluble peptide derivatives of the amyloid precursor protein (APP) can bind and activate GABAB1R in neurons, we found that the APP-derived peptide Aβ1-42 can increase maximal PTH secretion by parathyroid tissue in a CASR- and GABAB1R-dependent manner. VDR expression and serum vitamin D levels are inversely correlated with the relative abundance of APP, Aβ1-42, the γ- and β-secretases required for Aβ1-42 production, and the phosphorylated form of the microtubule associated protein Tau (pTau). Functionally, ablation of APP in the parathyroid abrogates the development of HPT in VDR KO mice, and inhibitors of Tau phosphorylation can block the ability of Aβ1-42 to promote PTH hypersecretion. These data suggest that HPT driven by loss of VDR activity could arise at least in part through unregulated expression of Aβ1-42 and pTau. Based on these findings, we hypothesize that aging-induced increases in Aβ1-42-mediated signaling drive tonic PTH hypersecretion and that vitamin D deficiency exacerbates HPT disease severity by relieving suppression of Aβ1-42 production and Tau/pTau expression. To test this model, we propose three complementary, mechanistic specific aims: (1) to delineate the molecular actions of Aβ1-42 on CaSR, GABAB1R, and downstream signaling events that promote PTH hypersecretion; (2) to determine whether blocking the production or activity of Aβ1-42 and Tau delays HPT development in a murine model of CaSR insufficiency; and (3) to delineate the causal relationship between VDR and Aβ1-42/pTau signaling in the parathyroid. By defining the contributions of the CaSR/GABAB1R/Aβ1-42 signaling axis to PTH hypersecretion, this work will provide a clearer mechanistic understanding of the unexpected connection between β-amyloid peptides, vitamin D status, and parathyroid gland function.