Recently, the Bell team from the University of California, San Diego, published an article titled: Transcriptional regulation by PHGDH drives' article on amyloid pathology in Alzheimer's disease The research team has revealed that a gene recently identified as a biomarker for Alzheimer's disease (AD) - PHGDH - is actually the key cause of the disease due to its previously unknown "moonlighting role". With the help of artificial intelligence technology, a small molecule drug candidate that can block the pathogenic pathway of this gene has been discovered.

The mystery of diseases that is difficult to explain by traditional genetic theories

Among people over 65 years old, about one in nine suffer from Alzheimer's disease. Although certain gene mutations can lead to hereditary AD, such cases account for only a very small number. The vast majority of patients belong to "sporadic AD", whose cause has long been unknown. At present, the treatment options for AD are very limited and the therapeutic effects are not satisfactory.

From biomarkers to the culprits causing the disease

The team previously discovered that the expression level of the PHGDH gene is directly related to the severity of brain lesions in AD patients: the more proteins and Rnas produced by this gene, the more severe the disease progression. This phenomenon has been verified in multiple independent queues. In the latest research, the team confirmed through mouse and human brain organ models that changes in PHGDH expression directly regulate the progression of AD - reducing its expression can delay the disease, while increasing its expression can accelerate the deterioration.

AI Unveils "Part-time Function" : A brand-new pathogenic mechanism of PHGDH

PHGDH was originally renowned for its enzymatic function in synthesizing serine, but experiments have shown that its pathogenic effect has nothing to do with the enzyme activity. With the help of AI three-dimensional structure prediction, the team unexpectedly discovered that there is A DNA-binding domain in the PHGDH protein (similar in structure to known transcription factors), which can directly activate the pro-inflammatory genes IKKα and HMGB1, disrupt the epigenetic balance of cells, and ultimately lead to the accumulation of beta-amyloid protein (Aβ).

"This discovery relies on AI's precise modeling of the three-dimensional structure of proteins," said Dr. Chen Junchen, the first author. "PHGDH induces spontaneous AD through a novel pathway and has nothing to do with its traditional metabolic function."

Small molecule drugs show therapeutic potential

Based on the mechanism research, the team screened out the small molecule NCT-503 that can penetrate the blood-brain barrier. AI simulation shows that this molecule can bind to the DNA-binding domain of PHGDH, blocking its transcriptional regulatory function. In the AD mouse model, NCT-503 treatment significantly reduced Aβ deposition and improved memory and anxiety symptoms. "Most existing therapies target advanced amyloid plaques, while our target is located in the upstream pathway and is expected to block the disease at its source," Zhong Sheng explained.

Clinical transformation prospects

Despite the limitations of current animal models, the Zhongsheng team believes that NCT-503 has preclinical development value. Compared with the existing therapies that require intravenous infusion, such small molecule drugs can be administered orally and have more application advantages. The next step will be to optimize the compound and initiate the FDA preclinical research.

Original link

https://www.cell.com/cell/fulltext/S0092-8674(25)00397-6?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867425003976%3Fshowall%3Dtrue