RNA-Binding Activity of PHGDH Drives Amyloid-beta Production in A Human Brain Organoid Model of Sporadic Alzheimer's Disease

Pathological progression in sporadic Alzheimer's disease (sAD) initiates with an early rise in soluble amyloid-ß (Aß), 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 Aß production through a previously unrecognized RNA-binding function. Specifically, PHGDH binds the 3'UTR of EIF2AK1 mRNA, enabling the physical interaction between PHGDH and the EIF2AK1 protein. By facilitating the recruitment of EIF2AK1 to its substrate EIF2a, this complex drives EIF2a phosphorylation, thereby selectively promoting the translation of BACE1, the rate-limiting enzyme for Aß generation. We demonstrate that PHGDH overexpression elevates BACE1 protein and intracellular Aß (iAß) 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 EIF2AK1 3'UTR. These findings define a PHGDH-EIF2AK1-EIF2a-BACE1 axis as a key driver of the earliest amyloid pathology in sAD. Overall design: RNA Immunoprecipitation-seq (RIP-seq) of PHGDH in H1 cell-derived brain organoids with or without human serum treatment. For each condition, 2 reaplicates are included.