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 ...