A groundbreaking study conducted by researchers at the University of California San Diego has uncovered a previously unknown role of the PHGDH gene in the development of Alzheimer’s disease. Using advanced artificial intelligence techniques, the team identified that this gene disrupts gene regulation in the brain through a hidden DNA-binding function, unrelated to its traditional enzymatic activity. This discovery not only sheds light on the early stages of Alzheimer's but also introduces a promising therapeutic candidate, NCT-503, which effectively blocks the harmful effects of PHGDH without disturbing normal brain chemistry. The findings were published in the journal Cell and offer hope for the prevention and treatment of spontaneous Alzheimer's disease.
The journey to understanding the role of PHGDH began with its identification as a potential biomarker for Alzheimer’s. Researchers observed that higher levels of PHGDH corresponded with more advanced stages of the disease, prompting further investigation into its causal relationship. Through experiments involving mice and human brain organoids, the team demonstrated that altering PHGDH expression directly influenced the progression of Alzheimer’s. Specifically, reducing PHGDH levels slowed the disease, while increasing them accelerated it.
Initially, the researchers believed that PHGDH's metabolic function was responsible for its connection to Alzheimer’s. However, their attempts to prove this hypothesis failed, leading them to explore alternative mechanisms. Inspiration came from another project in the lab, which revealed widespread imbalances in the brain's gene regulation process—a hallmark of Alzheimer’s. Leveraging modern AI tools, the team visualized the three-dimensional structure of PHGDH and discovered a substructure resembling known DNA-binding domains. This finding indicated that PHGDH could regulate critical target genes, disrupting the delicate balance necessary for healthy brain function.
This newly identified regulatory role of PHGDH operates independently of its enzymatic activity, providing a plausible explanation for its involvement in Alzheimer’s development. In Alzheimer’s patients, increased production of PHGDH proteins triggers these imbalances, contributing to the early onset of the disease. Understanding this mechanism paved the way for identifying potential treatments targeting the root cause rather than merely addressing symptoms.
In search of an effective intervention, the researchers turned their attention to NCT-503, a small molecule capable of penetrating the blood-brain barrier. Unlike other inhibitors, NCT-503 does not interfere with PHGDH’s enzymatic activity, preserving normal brain functions. Further analysis using AI confirmed that NCT-503 binds to the DNA-binding substructure of PHGDH, inhibiting its disruptive regulatory role. When tested in two mouse models of Alzheimer’s, NCT-503 significantly reduced disease progression and improved memory and anxiety-related behaviors.
Despite the promising results, the researchers acknowledge the limitations of their study, particularly the lack of a perfect animal model for spontaneous Alzheimer’s. Nevertheless, the efficacy of NCT-503 in existing models underscores its potential for further clinical development. Sheng Zhong, the senior author of the study, expressed optimism about the possibility of leveraging entirely new classes of small molecules for future therapeutics. These compounds could offer advantages over current treatments, such as oral administration instead of infusions.
The next phase involves optimizing NCT-503 and conducting FDA IND-enabling studies. This research highlights the importance of transcriptional regulation in late-onset Alzheimer’s and opens doors to innovative therapeutic strategies beyond targeting familial mutations. By unraveling the complex mechanisms underlying Alzheimer’s, scientists are one step closer to developing effective interventions for this debilitating disease.