Transcriptional regulation by PHGDH drives amyloid pathology in Alzheimer's disease

Junchen Chen; Fatemeh Hadi; Xingzhao Wen; Wenxin Zhao; Ming Xu; Shuanghong Xue; Pei Lin; Riccardo Calandrelli; John Lalith Charles Richard; Zhixuan Song; Jessica Li; Alborz Amani; Yang Liu; Xu Chen; Sheng Zhong

doi:10.1016/j.cell.2025.03.045

Transcriptional regulation by PHGDH drives amyloid pathology in Alzheimer's disease

Cell. 2025 Jun 26;188(13):3513-3529.e26. doi: 10.1016/j.cell.2025.03.045. Epub 2025 Apr 23.

Authors

Affiliations

¹ Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, La Jolla, San Diego, CA, USA.
² Institute of Engineering in Medicine, University of California, San Diego, La Jolla, San Diego, CA, USA.
³ Program in Bioinformatics and Systems Biology, University of California, San Diego, La Jolla, San Diego, CA, USA.
⁴ School of Biological Sciences, University of California, San Diego, La Jolla, San Diego, CA, USA.
⁵ Department of Neurosciences, University of California, San Diego, La Jolla, San Diego, CA, USA; Neuroscience Graduate Program, University of California, San Diego, La Jolla, San Diego, CA, USA.
⁶ Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, La Jolla, San Diego, CA, USA; Institute of Engineering in Medicine, University of California, San Diego, La Jolla, San Diego, CA, USA; Program in Bioinformatics and Systems Biology, University of California, San Diego, La Jolla, San Diego, CA, USA; Neuroscience Graduate Program, University of California, San Diego, La Jolla, San Diego, CA, USA. Electronic address: szhong@ucsd.edu.

Abstract

Virtually all individuals aged 65 or older develop at least early pathology of Alzheimer's disease (AD), yet most lack disease-causing mutations in APP, PSEN, or MAPT, and many do not carry the APOE4 risk allele. This raises questions about AD development in the general population. Although transcriptional dysregulation has not traditionally been a hallmark of AD, recent studies reveal significant epigenomic changes in late-onset AD (LOAD) patients. We show that altered expression of the LOAD biomarker phosphoglycerate dehydrogenase (PHGDH) modulates AD pathology in mice and human brain organoids independent of its enzymatic activity. PHGDH has an uncharacterized role in transcriptional regulation, promoting the transcription of inhibitor of nuclear factor kappa-B kinase subunit alpha (IKKa) and high-mobility group box 1 (HMGB1) in astrocytes, which suppress autophagy and accelerate amyloid pathology. A blood-brain-barrier-permeable small-molecule inhibitor targeting PHGDH's transcriptional function reduces amyloid pathology and improves AD-related behavioral deficits. These findings highlight transcriptional regulation in LOAD and suggest therapeutic strategies beyond targeting familial mutations.

Keywords: Alzheimer’s disease; LOAD; PHGDH; amyloid pathology; astrocyte; biomarker; small molecule; therapeutic candidate; transcriptional regulation.

MeSH terms

Aged
Alzheimer Disease* / genetics
Alzheimer Disease* / metabolism
Alzheimer Disease* / pathology
Amyloid* / metabolism
Animals
Astrocytes / metabolism
Brain / metabolism
Brain / pathology
Disease Models, Animal
Female
Gene Expression Regulation
Humans
Male
Mice
Mice, Transgenic
Phosphoglycerate Dehydrogenase* / antagonists & inhibitors
Phosphoglycerate Dehydrogenase* / genetics
Phosphoglycerate Dehydrogenase* / metabolism
Transcription, Genetic

Substances

Phosphoglycerate Dehydrogenase
Amyloid

Abstract

MeSH terms

Substances

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