{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:29:24Z","timestamp":1768570164014,"version":"3.49.0"},"posted":{"date-parts":[[2025,5,28]]},"group-title":"Endocrinology (including Diabetes Mellitus and Metabolic Disease)","reference-count":39,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T00:00:00Z","timestamp":1748390400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  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 \u03b3-aminobutyric acid receptor 1 (GABA\n                  <jats:sub>B1<\/jats:sub>\n                  R) with the extracellular Ca\n                  <jats:sup>2+<\/jats:sup>\n                  -sensing receptor (CaSR) in parathyroid cells; however, endogenous activators of the heterodimers are unknown. Here we uncovered increased expression of the \u03b2-amyloid peptide (A\u03b2\n                  <jats:sub>42<\/jats:sub>\n                  ) cleaved from the amyloid precursor protein in parathyroid cells from PHPT patients and aging mice, and the ability of exogenous A\u03b2\n                  <jats:sub>42<\/jats:sub>\n                  to promote tonic PTH secretion from murine or human parathyroid glands\n                  <jats:italic>ex vivo<\/jats:italic>\n                  . Conversely, parathyroid-specific\n                  <jats:italic>App<\/jats:italic>\n                  gene knockout reduced tonic PTH secretion and lowered serum PTH levels in mice. The absence of an A\u03b2\n                  <jats:sub>42<\/jats:sub>\n                  effect on PTH secretion in parathyroid glands lacking CaSR or GABA\n                  <jats:sub>B1<\/jats:sub>\n                  R supports direct interactions between A\u03b2\n                  <jats:sub>42<\/jats:sub>\n                  and the heterodimer.\n                  <jats:italic>In situ<\/jats:italic>\n                  proteomic profiling of parathyroid glands from PHPT patients closely correlated lower serum 25-hydroxyvitamin D levels with increased GABA\n                  <jats:sub>B1<\/jats:sub>\n                  R \/CaSR heterodimer expression, \u03b2-amyloidogenesis, and phosphorylation of Tau, a downstream effector of A\u03b2\n                  <jats:sub>42<\/jats:sub>\n                  . Concurrent ablation of\n                  <jats:italic>App<\/jats:italic>\n                  or the Tau-encoding\n                  <jats:italic>Mapt<\/jats:italic>\n                  gene prevented tonic PTH hypersecretion in parathyroid-specific\n                  <jats:italic>Vdr<\/jats:italic>\n                  -KO mice. Likewise, weekly administration of an A\u03b2\n                  <jats:sub>42<\/jats:sub>\n                  -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\u03b2\n                  <jats:sub>42<\/jats:sub>\n                  in driving tonic PTH secretion by activating GABA\n                  <jats:sub>B1<\/jats:sub>\n                  R\/CaSR heterodimers and suggest the potential for targeting A\u03b2\n                  <jats:sub>42<\/jats:sub>\n                  in PHPT treatment.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>\n                    Blocking aberrant signaling through A\u03b2, the GABA\n                    <jats:sub>B1<\/jats:sub>\n                    R\/CaSR dimer, and Tau can suppress tonic PTH hypersecretion in hyperparathyroidism associated with vitamin D deficiency.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.27.25328314","type":"posted-content","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T01:20:19Z","timestamp":1748481619000},"source":"Crossref","is-referenced-by-count":0,"title":["\u03b2-Amyloid as a new target to suppress tonic PTH hypersecretion in primary hyperparathyroidism"],"prefix":"10.64898","author":[{"given":"Chia-Ling","family":"Tu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiqiang","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas","family":"Szeto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sofya","family":"Savransky","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timofey","family":"Glinin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dolores M.","family":"Shoback","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie A.","family":"Sosa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Pierre","family":"Vilardaga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Koh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenhan","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025053005151042000_2025.05.27.25328314v1.1","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1111\/jgs.12968","article-title":"Surgical management of primary hyperparathyroidism in older adults","volume":"62","year":"2014","journal-title":"J Am Geriatr Soc"},{"key":"2025053005151042000_2025.05.27.25328314v1.2","doi-asserted-by":"publisher","DOI":"10.1093\/ageing\/afg122"},{"key":"2025053005151042000_2025.05.27.25328314v1.3","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-4022"},{"key":"2025053005151042000_2025.05.27.25328314v1.4","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1001\/jamasurg.2019.3950","article-title":"Parathyroidectomy for Patients With Primary Hyperparathyroidism and Associations With Hypertension","volume":"155","year":"2020","journal-title":"JAMA Surg"},{"key":"2025053005151042000_2025.05.27.25328314v1.5","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2010-0158"},{"key":"2025053005151042000_2025.05.27.25328314v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)60507-9"},{"key":"2025053005151042000_2025.05.27.25328314v1.7","doi-asserted-by":"crossref","first-page":"3168","DOI":"10.1210\/clinem\/dgab524","article-title":"Ex Vivo Intact Tissue Analysis Reveals Alternative Calcium-sensing Behaviors in Parathyroid Adenomas","volume":"106","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"2025053005151042000_2025.05.27.25328314v1.8","unstructured":"C.-L. 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