Amyloid-β as a target to suppress tonic PTH hypersecretion in hyperparathyroidism due to vitamin D deficiency

Hyperparathyroidism is an endocrine disorder linked to vitamin D deficiency. Reduced vitamin D receptor (VDR) activity promotes parathyroid hormone (PTH) hypersecretion by increasing heterodimerization of the type B γ-aminobutyric acid receptor 1 (GABA_B1R) with the extracellular Ca²⁺-sensing receptor (CaSR) in parathyroid cells; however, endogenous activators of the heterodimers are unknown. We uncovered increased expression of amyloid-β peptide cleaved from the amyloid-β precursor protein (APP) in parathyroid cells of patients with hyperparathyroidism and aging mice manifesting vitamin D deficiency and the ability of exogenous amyloid-β to promote tonic PTH secretion from cultured murine or human parathyroid glands. Conversely, parathyroid cell-specific App gene deletion reduced tonic PTH secretion and lowered serum PTH concentrations in mice. The absence of the amyloid-β effect on PTH secretion in parathyroid cells lacking CaSR or GABA_B1R supported direct interactions of amyloid-β with the receptor heterodimers. In situ proteomic profiling of parathyroid cells of patients with hyperparathyroidism correlated lower serum 25-hydroxyvitamin D concentrations with increased GABA_B1R/CaSR heterodimer expression, β-amyloidogenesis, and phosphorylation of Tau, a downstream effector of amyloid-β. Concurrent ablation of App or the Tau-encoding Mapt gene prevented tonic PTH hypersecretion in parathyroid cell-specific Vdr knockout mice. Likewise, weekly administration of an amyloid-β-neutralizing antibody suppressed tonic PTH hypersecretion and synergized with daily administration of cinacalcet, which activates CaSR homodimers, to reduce serum PTH concentrations in aged mice. These data demonstrated amyloid-β actions in driving tonic PTH secretion by activating GABA_B1R/CaSR heterodimers and the potential of targeting amyloid-β to treat hyperparathyroidism due to vitamin D deficiency.