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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,2,24]]},"abstract":"<jats:p>\n                    Pathological progression in sporadic Alzheimer\u2019s disease (sAD) initiates with an early rise in soluble amyloid-\u03b2 (A\u03b2), preceding plaque formation and neurodegeneration. However, the molecular event triggering this initial accumulation remains unknown. We report that phosphoglycerate dehydrogenase (PHGDH), a consistent biomarker of prodromal sAD, drives A\u03b2 production through a previously unrecognized RNA-binding function. Specifically, PHGDH binds the 3\u2032UTR of\n                    <jats:italic toggle=\"yes\">EIF2AK1<\/jats:italic>\n                    mRNA, enabling the physical interaction between PHGDH and the EIF2AK1 protein. By facilitating the recruitment of EIF2AK1 to its substrate EIF2\u03b1, this complex drives EIF2\u03b1 phosphorylation, thereby selectively promoting the translation of BACE1, the rate-limiting enzyme for A\u03b2 generation. We demonstrate that PHGDH overexpression elevates BACE1 protein and intracellular A\u03b2 in neurons and astrocytes across mouse models and human brain organoids, independent of its canonical enzymatic or transcriptional roles. Mechanistically, this process requires a specific RNA-binding surface within PHGDH and the\n                    <jats:italic toggle=\"yes\">EIF2AK1<\/jats:italic>\n                    3\u2032UTR. These findings define a PHGDH\u2013EIF2AK1\u2013EIF2\u03b1\u2013BACE1 axis as a key driver of the earliest amyloid pathology in sAD.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2532234123","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T19:07:46Z","timestamp":1771355266000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["RNA-binding activity of PHGDH drives amyloid-beta production in a human brain organoid model of sporadic Alzheimer\u2019s disease"],"prefix":"10.1073","volume":"123","author":[{"given":"Junchen","family":"Chen","sequence":"first","affiliation":[{"name":"Shu Chien-Gene Lay Department of Bioengineering, University of California San Diego","place":["La Jolla"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Engineering in Medicine, University of California San 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