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 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 (p0.001 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, p0.0001), 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