OR23-01 The Nonredundant Role Of Beta-Amyloid In Mediating Tonic PTH Secretion In Physiological And Pathological States

Disclosure: C. Tu: None. Z. Cheng: None. K.A. Pena: None. N. Szeto: None. J.A. Sosa: None. J. Vilardaga: None. J. Koh: None. W. Chang: None. Understanding the mechanisms driving parathyroid hormone (PTH) hypersecretion in primary hyperparathyroidism (PHPT) is essential for better management of this common endocrinopathy. Prior studies showed that reduced Ca(2+)-sensing receptor (CaSR) expression and the subsequent increases in heterodimerization of the CaSR with the type B γ-aminobutyric acid receptor 1 (GABA(B1)R) are causally linked to PTH hypersecretion in PHPT mouse models (Nat Metab 2:243-255). We further showed that expression of the putative GABA(B1)R ligands, amyloid precursor protein (APP) and its proteolytic product, β-amyloid (Aβ(1-42)), is significantly upregulated in adenomas of PHPT patients associated with vitamin D insufficiency/deficiency when compared to normal donor controls. The current study aims to delineate the actions of Aβ(1-42) in promoting tonic PTH secretion and its interactions with vitamin D receptor (VDR) signaling in parathyroid glands (PTGs) in basal and PHPT states. We show that Aβ(1-42) (200 nM) stimulated tonic PTH secretion in cultures of normal human PTGs without shifting the calcium/PTH secretion setpoint (Ca(2+)-setpoint). In contrast, conditional knockout (KO) of the App gene in the parathyroid cell (PTC) of (PTC)App(Δflox/Δflox) mice significantly reduced serum PTH levels (KO: 64±13 pg/ml vs Control: 109±12 pg/ml; p<0.05, n=8) despite hypocalcemia, indicating hypoparathyroidism. In PTGs cultured from the (PTC)App(Δflox/Δflox) mice, supplementation of Aβ(1-42) dose-dependently (EC(50)=5.6 nM, p<0.001) increased PTH secretion without altering the Ca(2+)-setpoint. However, the stimulatory effects of Aβ(1-42) on tonic PTH secretion were completely abrogated in the PTGs with concurrent deletions of App, Casr and Gabbr1 genes, supporting a direct action of Aβ(1-42) on CaSR and/or GABA(B1)R. The latter notion is further supported by the ability of Aβ(1-42) to stimulate cAMP production in cells co-expressing CaSR and GABA(B1)R. PTC-specific deletion of the Vdr gene in the (PTC)Vdr(Δflox/Δflox) mice led to elevated serum PTH levels in vivo and increased tonic PTH secretion with unaffected Ca(2+)-setpoint in PTGs in vitro. Concurrent ablation of the App gene completely normalized serum PTH levels in the (PTC)Vdr(Δflox/Δflox) mice and prevented PTH hypersecretion in their PTGs in culture. These findings support a critical role of the APP-derived Aβ(1-42) in mediating tonic PTH secretion in the normal physiological state and suggest a new mechanism driving PTH hypersecretion in PHPT due to vitamin D deficiency. Presentation: Saturday, June 17, 2023