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_B1R) 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 β-amyloid peptide (Aβ₄₂) cleaved from the amyloid precursor protein in parathyroid cells from PHPT patients and aging mice, and the ability of exogenous Aβ₄₂to promote tonic PTH secretion from murine or human parathyroid glandsex vivo. Conversely, parathyroid-specificAppgene knockout reduced tonic PTH secretion and lowered serum PTH levels in mice. The absence of an Aβ₄₂effect on PTH secretion in parathyroid glands lacking CaSR or GABA_B1R supports direct interactions between Aβ₄₂and the heterodimer.In situproteomic profiling of parathyroid glands from PHPT patients closely correlated lower serum 25-hydroxyvitamin D levels with increased GABA_B1R /CaSR heterodimer expression, β-amyloidogenesis, and phosphorylation of Tau, a downstream effector of Aβ₄₂. Concurrent ablation ofAppor the Tau-encodingMaptgene prevented tonic PTH hypersecretion in parathyroid-specificVdr-KO mice. Likewise, weekly administration of an Aβ₄₂-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 Aβ₄₂in driving tonic PTH secretion by activating GABA_B1R/CaSR heterodimers and suggest the potential for targeting Aβ₄₂in PHPT treatment.