Transcriptional Regulation by PHGDH Modulates Pathological Progression in a Human Brain Organoid Model of Late-Onset Alzheimer’s Disease

Phosphoglycerate Dehydrogenase (PHGDH), prominently expressed in brain astrocytes, exhibits heightened levels in the early stages of late-onset Alzheimer’s Disease (LOAD). We demonstrate that alterations in PHGDH expression within astrocytes in a human brain organoid model of LOAD induce pathological changes, independent of PHGDH’s canonical enzymatic role. Remarkably, PHGDH functions as a transcriptional regulator by binding to chromatin, as evidenced by ChIP-seq, snRNA-seq, knockdown, and mutation experiments. Our analysis identifies IKKa and HMGB1, regulators of NFκB and autophagy, as pivotal transcriptional targets of PHGDH. Dual knockdown of IKKa and HMGB1 in astrocytes effectively mitigates PHGDH-induced LOAD pathological changes in brain organoids, reducing Aβ aggregates, cell death, and NFκB activation while enhancing synaptic puncta and autophagy. These findings unveil a novel pathological pathway in LOAD, elucidating PHGDH’s role as a transcriptional regulator in disease progression. To explore PHGDH's role as a transcriptional regulator, we conducted PHGDH ChIP-seq and scRNA-seq analyses in brain organoids. Our samples included normal cultured organoids, serum-induced sporadic AD brain organoids, and sporadic AD brain organoids with astrocyte-specific PHGDH knockdown.