β-Amyloid as a new target to suppress tonic PTH hypersecretion in primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder of aging closely linked to vitamin D deficiency. Reduced vitamin D receptor activities promote parathyroid hormone (PTH) hypersecretion by increasing the heterodimerization of the type B γ-aminobutyric acid receptor 1 (GABA(B1)R) with the extracellular Ca(2+)-sensing receptor (CaSR) in parathyroid cells; however, endogenous activators of the heterodimers are unknown. Here we uncovered increased expression of the β-amyloid peptide (Aβ(42)) cleaved from the amyloid precursor protein in parathyroid cells from PHPT patients and aging mice, and the ability of exogenous Aβ(42) to promote tonic PTH secretion from murine or human parathyroid glands ex vivo. Conversely, parathyroid-specific App gene knockout reduced tonic PTH secretion and lowered serum PTH levels in mice. The absence of an Aβ(42) effect on PTH secretion in parathyroid glands lacking CaSR or GABA(B1)R supports direct interactions between Aβ(42) and the heterodimer. In situ proteomic profiling of parathyroid glands from PHPT patients closely correlated lower serum 25-hydroxyvitamin D levels with increased GABA(B1)R /CaSR heterodimer expression, β-amyloidogenesis, and phosphorylation of Tau, a downstream effector of Aβ(42). Concurrent ablation of App or the Tau-encoding Mapt gene prevented tonic PTH hypersecretion in parathyroid-specific Vdr-KO mice. Likewise, weekly administration of an Aβ(42)-neutralizing antibody suppressed tonic PTH hypersecretion and synergized with daily administration of cinacalcet, a calcimimetic that activates CaSR homodimers, to reduce serum PTH levels in aging-induced hyperparathyroidism (HPT) mice. These data demonstrated novel functions of Aβ(42) in driving tonic PTH secretion by activating GABA(B1)R/CaSR heterodimers and suggest the potential for targeting Aβ(42) in PHPT treatment.