A new study has found that a gene recently recognized as a biomarker for Alzheimer’s disease is actually a cause of the disease due to its previously unknown secondary function. Researchers at the University of California, San Diego used artificial intelligence to solve this Alzheimer’s disease mystery and discover a possible treatment that prevents the gene’s dual function. The research team published their findings in the journal Cell.
PHGDH is a Causative Gene for Spontaneous Alzheimer’s Disease
Around one in nine people over the age of 65 suffers from Alzheimer’s disease, the most common cause of dementia. Although certain genes can lead to Alzheimer’s if they are mutated, this link only accounts for a small percentage of all Alzheimer’s patients. The vast majority of patients do not have a mutation in a known disease-causing gene, but suffer from “spontaneous” Alzheimer’s, the causes of which are unclear. The discovery of these causes could ultimately improve medical care. “Unfortunately, the treatment options for Alzheimer’s are very limited. And treatment outcomes are currently not very good,” said the study’s lead author Sheng Zhong, professor at the Shu Chien-Gene Lay Department of Bioengineering at the UC San Diego Jacobs School of Engineering.
Zhong and his team therefore took a closer look at phosphoglycerate dehydrogenase (PHGDH), which they had previously discovered as a potential blood biomarker for the early detection of Alzheimer’s disease. In a follow-up study, they later discovered that the expression levels of the PHGDH gene aredirectly linked to changes in the brain in Alzheimer’s disease. In other words, the higher the protein and RNA levels produced by the PHGDH gene, the more advanced the disease. According to Zhong, this correlation has since been confirmed in several cohorts from different medical centers.
Intrigued by this reproducible correlation, the research team decided to investigate whether a causal relationship exists in this current study. Using mice and human brain organoids, the researchers found that a change in PHGDH expression has a significant impact on Alzheimer’s disease: Lower levels correlated with slower progression of the disease, while higher levels led to faster progression. Thus, the researchers were able to prove that PHGDH is indeed a causative gene for spontaneous Alzheimer’s disease. To further substantiate this finding, the researchers used AI to determine that PHGDH plays a previously unknown role: It triggers a signaling pathway that disrupts gene activation in brain cells. Such a disruption can lead to problems such as the development of Alzheimer’s disease.
How Researchers Used Modern AI
PHGDH forms an enzyme that is essential for the production of serine, an essential amino acid and neurotransmitter. Since the enzymatic activity of PHGDH was its only known function, the researchers hypothesized that its metabolic function must be related to Alzheimer’s disease. However, all experiments designed to prove this failed. However, another Alzheimer’s project in Zhong’s lab, which did not focus on PHGDH, changed everything. A year ago, this project discovered a characteristic feature of Alzheimer’s disease: a widespread imbalance in the brain in the process by which cells control which genes are activated or deactivated to perform their specific tasks. The researchers were curious to see if PHGDH plays an unknown regulatory role in this process and turned to modern AI for help. Using AI, they were able to visualize the three-dimensional structure of the PHGDH protein. Within this structure, they discovered that the protein has a substructure that is very similar to a known DNA-binding domain in a class of known transcription factors. The similarity is only in the structure and not in the protein sequence.
After discovering the substructure, the team was able to show that the protein can activate two important target genes. This upsets the delicate balance, leading to several problems and ultimately to the early stages of Alzheimer’s disease. In other words, PHGDH has a previously unknown role, independent of its enzymatic function, that leads to spontaneous Alzheimer’s disease via a novel pathway. This follows on from earlier studies by the team: The PHGDH gene produced more proteins in the brains of Alzheimer’s patients than in the brains of the control group, and these increased protein levels in the brain triggered the imbalance. Although everyone has the PHGDH gene, the difference lies in the expression level of the gene, i.e. how many proteins are produced.
Possible Treatment Option
Once the researchers had uncovered the mechanism, they wanted to find out how to intervene and potentially identify a therapeutic drug candidate that could help fight the disease. While many current treatments focus on treating the abnormal accumulation of the sticky protein beta-amyloid in the brain, some studies suggest that treating these plaques may be ineffective: At this stage of accumulation, treatment is essentially too late. However, the critical signaling pathway discovered in this study is further upstream, so interrupting this pathway may reduce the formation of amyloid plaques in the first place.
Because PHGDH is such an important enzyme, there have been previous studies on potential inhibitors. A small molecule called NCT-503 caught the researchers’ eye because it does not completely inhibit the enzymatic activity of PHGDH (the production of serine), which is not what they wanted. NCT-503 is also able to cross the blood-brain barrier, which is a desirable property. For three-dimensional visualization and modeling, they again resorted to AI. They found that NCT-503 has access to this DNA-binding substructure of PHGDH thanks to a binding site. Further tests confirmed that NCT-503 indeed inhibits the regulatory function of PHGDH. When the researchers tested NCT-503 in two mouse models of Alzheimer’s disease, they found that it significantly slowed the progression of the disease. The treated mice showed significant improvement in memory and anxiety tests. These tests were chosen because Alzheimer’s patients suffer from cognitive decline and increased anxiety.
However, the researchers also acknowledge the limitations of their study. One of these is that there is no perfect animal model for spontaneous Alzheimer’s disease. They were only able to test NCT-503 in the available mouse models with mutations in the known disease-causing genes. Nevertheless, the results are promising, according to Zhong. According to the researchers, there may be completely new classes of small molecules that can be used for the development of future therapeutics. One advantage of small molecules is that they can even be administered orally, unlike current treatments that require infusions. The next steps are to optimize the compound and test it in studies that will allow it to be approved as an Investigational New Drug (IND) by the FDA.