A novel link between vitamin D deficiency, beta-amyloid protein signaling, and aging in the development of parathyroid tumors

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.  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 (GABA_B1R) can form heterodimeric complexes with CaSR, promoting parathyroid hormone (PTH) hypersecretion by opposing the coupling of CaSR with its obligate downstream G-protein effectors G_q/11 and G_i. Second, building upon a recent report demonstrating that soluble peptide derivatives of the amyloid precursor protein (APP) can bind and activate GABA_B1R in neurons, we found that the APP-derived peptide Ab_1-42 can increase maximal PTH secretion by parathyroid tissue in a CASR- and GABA_B1R-dependent manner. VDR expression and serum vitamin D levels are inversely correlated with the relative abundance of APP, Ab_1-42, the g- and b-secretases required for Ab_1-42 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 Ab_1-42 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 Ab_1-42 and pTau. Based on these findings, we hypothesize that aging-induced increases in Ab_1-42-mediated signaling drive tonic PTH hypersecretion and that vitamin D deficiency exacerbates HPT disease severity by relieving suppression of Ab_1-42 production and Tau/pTau expression. We are currently testing this model through three complementary experimental approaches: (1) delineating the molecular actions of Ab_1-42 on CaSR, GABA_B1R, and downstream signaling events that promote PTH hypersecretion; (2) determinng whether blocking the production or activity of Ab_1-42 and Tau delays HPT development in a murine model of CaSR insufficiency; and (3) elucidating the causal relationship between VDR and Ab_1-42/pTau signaling in the parathyroid.  By defining the contributions of the CaSR/GABA_B1R/Ab1-42 signaling axis to PTH hypersecretion, this work will provide a clearer understanding of the unexpected connection between b-amyloid peptides, vitamin D status, and parathyroid gland function. 

This work is supported by NIH grants 1R21AG070721 and 1RF1AG075742.

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