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 {gamma}-aminobutyric acid receptor 1 (GABAB1R) with the extracellular Ca2+-sensing receptor (CaSR) in parathyroid cells; however, endogenous activators of the heterodimers are unknown. Here we uncovered increased expression of the {beta}-amyloid peptide (A{beta}42) cleaved from the amyloid precursor protein in parathyroid cells from PHPT patients and aging mice, and the ability of exogenous A{beta}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 A{beta}42 effect on PTH secretion in parathyroid glands lacking CaSR or GABAB1R supports direct interactions between A{beta}42 and the heterodimer. In situ proteomic profiling of parathyroid glands from PHPT patients closely correlated lower serum 25-hydroxyvitamin D levels with increased GABAB1R /CaSR heterodimer expression, {beta}-amyloidogenesis, and phosphorylation of Tau, a downstream effector of A{beta}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 A{beta}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 A{beta}42 in driving tonic PTH secretion by activating GABAB1R/CaSR heterodimers and suggest the potential for targeting A{beta}42 in PHPT treatment. One Sentence SummaryBlocking aberrant signaling through A{beta}, the GABAB1R/CaSR dimer, and Tau can suppress tonic PTH hypersecretion in hyperparathyroidism associated with vitamin D deficiency.