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Transl. Med."],"published-print":{"date-parts":[[2026,3,18]]},"abstract":"<jats:p>\n                    Hyperparathyroidism is an endocrine disorder linked to vitamin D deficiency. Reduced vitamin D receptor (VDR) activity promotes parathyroid hormone (PTH) hypersecretion by increasing 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. We uncovered increased expression of amyloid-\u03b2 peptide cleaved from the amyloid-\u03b2 precursor protein (APP) in parathyroid cells of patients with hyperparathyroidism and aging mice manifesting vitamin D deficiency and the ability of exogenous amyloid-\u03b2 to promote tonic PTH secretion from cultured murine or human parathyroid glands. Conversely, parathyroid cell\u2013specific\n                    <jats:italic toggle=\"yes\">App<\/jats:italic>\n                    gene deletion reduced tonic PTH secretion and lowered serum PTH concentrations in mice. The absence of the amyloid-\u03b2 effect on PTH secretion in parathyroid cells lacking CaSR or GABA\n                    <jats:sub>B1<\/jats:sub>\n                    R supported direct interactions of amyloid-\u03b2 with the receptor heterodimers. In situ proteomic profiling of parathyroid cells of patients with hyperparathyroidism correlated lower serum 25-hydroxyvitamin D concentrations with increased GABA\n                    <jats:sub>B1<\/jats:sub>\n                    R\/CaSR heterodimer expression, \u03b2-amyloidogenesis, and phosphorylation of Tau, a downstream effector of amyloid-\u03b2. Concurrent ablation of\n                    <jats:italic toggle=\"yes\">App<\/jats:italic>\n                    or the Tau-encoding\n                    <jats:italic toggle=\"yes\">Mapt<\/jats:italic>\n                    gene prevented tonic PTH hypersecretion in parathyroid cell\u2013specific\n                    <jats:italic toggle=\"yes\">Vdr<\/jats:italic>\n                    knockout mice. Likewise, weekly administration of an amyloid-\u03b2\u2013neutralizing antibody suppressed tonic PTH hypersecretion and synergized with daily administration of cinacalcet, which activates CaSR homodimers, to reduce serum PTH concentrations in aged mice. These data demonstrated amyloid-\u03b2 actions in driving tonic PTH secretion by activating GABA\n                    <jats:sub>B1<\/jats:sub>\n                    R\/CaSR heterodimers and the potential of targeting amyloid-\u03b2 to treat hyperparathyroidism due to vitamin D deficiency.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adz2837","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T17:58:36Z","timestamp":1773856716000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Amyloid-\u03b2 as a target to suppress tonic PTH hypersecretion in hyperparathyroidism due to vitamin D deficiency"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7323-7733","authenticated-orcid":true,"given":"Chia-Ling","family":"Tu","sequence":"first","affiliation":[{"name":"Endocrine Research Unit, San Francisco VA Medical Center, and Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiqiang","family":"Cheng","sequence":"additional","affiliation":[{"name":"Endocrine Research Unit, San Francisco VA Medical Center, and Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas","family":"Szeto","sequence":"additional","affiliation":[{"name":"Endocrine Research Unit, San Francisco VA Medical Center, and Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1495-7412","authenticated-orcid":true,"given":"Sofya","family":"Savransky","sequence":"additional","affiliation":[{"name":"Laboratory for GPCR Biology, Department of Pharmacology &amp; Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA."},{"name":"Graduate Program in Molecular Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0550-741X","authenticated-orcid":true,"given":"Timofey","family":"Glinin","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7602-8409","authenticated-orcid":true,"given":"Amanda","family":"Herberger","sequence":"additional","affiliation":[{"name":"Endocrine Research Unit, San Francisco VA Medical Center, and Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2936-4468","authenticated-orcid":true,"given":"Dolores M.","family":"Shoback","sequence":"additional","affiliation":[{"name":"Endocrine Research Unit, San Francisco VA Medical Center, and Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3356-7316","authenticated-orcid":true,"given":"Julie A.","family":"Sosa","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1217-1435","authenticated-orcid":true,"given":"Jean-Pierre","family":"Vilardaga","sequence":"additional","affiliation":[{"name":"Laboratory for GPCR Biology, Department of Pharmacology &amp; 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