7052 Beta-Amyloid Mediates PTH Hypersecretion In Hyperparathyroidism Associated With Vitamin D Deficiency

Abstract Disclosure: C. Tu: None. Z. Cheng: None. K.A. Pena: None. S. Savransky: None. T. Glinin: None. N. Szeto: None. J.A. Sosa: Research Investigator; Self; Institutional research funding and Data Monitoring Committee of the Medullary Thyroid Cancer Consortium Registry, supported by, AstraZeneca, Novo Nordisk, Eli Lilly & Company, Exelixis, Inc.. J. Vilardaga: None. J. Koh: None. W. Chang: None. Primary hyperparathyroidism (PHPT) is a common endocrinopathy characterized by elevated parathyroid hormone (PTH) secretion. Low serum 25-hydroxyvitamin D (25OHD) levels are more prevalent in PHPT patients than in the general population, however, the mechanistic basis for this association is unclear. Previous studies (Nat Metab 2:243) demonstrated that increased heterodimerization and co-activation (by GABA and Ca2+, respectively) of the type B γ-aminobutyric acid receptor 1 (GABAB1R) and the extracellular Ca2+-sensing receptor (CaSR) promote tonic PTH secretion from the parathyroid glands (PTGs) isolated from PHPT patients and HPT mice. In searching for additional ligands of the GABAB1R/CaSR heterodimer, we found upregulation of a putative GABAB1R ligand, the amyloid precursor protein (APP), and one of its derivatives, β-amyloid (Aβ1-42) in the parathyroid adenoma of PHPT patients verse age-matched normal PTGs (p<0.005) by in situ proteomic profiling. Those tumors also showed increased levels of the proteolytic enzymes, β-secretase and γ-secretase, that make Aβ1-42 and enhanced phosphorylation of the microtubule-associated protein TAU, a downstream effector of Aβ1-42-induced signaling in the degenerative neurons of dementia patients. Adding exogenous Aβ1-42 (0.3 to 1000 nM) in cultures concentration-dependently stimulated tonic PTH secretion by up to 1.6-fold in murine (p<0.001 vs control) and 1.9-fold in human PTGs (p=0.03 vs control) without shifting the Ca2+-set point. This stimulatory effect was absent in murine PTGs lacking either CaSR or GABAB1R. Furthermore, parathyroid cell (PTC)-specific knockout (KO) of the App (PTCAppΔflox/Δflox) gene to remove Aβ1-42 or the Gabbr1 (PTCGabbr1Δflox/Δflox) gene to disrupt GABAB1R/CaSR heterodimer similarly reduced tonic PTH secretion in PTG cultures and produced hypoparathyroidism in vivo, supporting a role for Aβ1-42 as a ligand in stimulating PTH secretion via GABAB1R/CaSR heterodimer. The proteomic profiles revealed a significant inverse correlation between the pre-operative 25OHD levels of PHPT patients and increased Tau phosphorylation in their PTG tumors (r2=0.225, p<0.0001), suggesting a role for Tau signaling in stimulating PTH secretion in 25OHD deficiency. In support of this idea, inhibition of Tau phosphorylation by a staurosporine analogue (K252a) blocked the ability of Aβ1-42 to stimulate PTH secretion in vitro, and the increased tonic PTH hypersecretion seen in mice with PTC-targeted Vdr gene KO (PTCVdrΔflox/Δflox), mimicking vitamin D deficiency, was reversed by a concurrent ablation of App (PTCVdrΔflox/Δflox;AppΔflox/Δflox) or the TAU-encoding Mapt (PTCVdrΔflox/Δflox;Mapt-/-) gene. Collectively, we demonstrate novel roles of Aβ1-42/p-Tau signaling in sustaining tonic PTH secretion in physiological states and in promoting PTH hypersecretion due to 25OHD deficiency. Presentation: 6/3/2024