Summary: Researchers have discovered that PHGDH, a gene that was originally thought to be a marker for Alzheimer’s illness, actually has a direct impact by impairing gene regulation in the mind. Using AI, the group revealed that PHGDH has a hidden DNA-binding work related to its known metabolic activity.
This defect provides a novel target for elimination and first Alzheimer’s disease development. A little protein, NCT-503, was also discovered that prevents this harmful activity without impairing brain function.
Important Facts:
- Hidden Role of PHGDH: AI revealed that PHGDH functions as a DNA-binding blaster, which causes Alzheimer’s.
- New Therapeutic Candidate: The small atom NCT-503 prevents the damaging work without affecting regular activity.
- Promising Outcomes: Treated mice showed storage and stress improvements, suggesting medical potential.
Origin: UCSD
A recent study revealed that a gene that was recently unexplored as a biomarker for Alzheimer’s disease really serves as its primary cause.
Researchers at the University of California San Diego used artificial knowledge to support both understand this secret of Alzheimer’s disease and learn a possible treatment that obstructs the gene’s freelance role.
The study group published their findings on April 23 in the journal , Cell.  ,
Alzheimer’s disease, the most prevalent cause of delirium, affects one in nine people over the age of 65. While most particular chromosomes, when mutated, can lead to Alzheimer’s, that relationship only accounts for a small percentage of all Alzheimer’s patients.
The majority of patients have” spontaneous” Alzheimer’s, but the causes of which are still undetermined, versus” spontaneous” Alzheimer’s, which is not a known disease-causing gene.
Finding those reasons was finally improve health care.
” However, treatment options for Alzheimer’s disease are very limited. And the outcomes of the study are” not remarkable at this time,” said senior author Sheng Zhong, a teacher in the Shu Chien-Gene Lay Department of Bioengineering at the UC San Diego Jacobs School of Engineering.
Therefore, Zhong and his team examined phosphoglycerate dehydrogenase ( PHGDH), which they had previously identified as a potential blood biomarker, for the early diagnosis of Alzheimer’s disease.
In a follow-up study, they afterwards found that , appearance levels of the PHGDH protein immediately correlated , with changes in the brain in Alzheimer’s disease, in other words, the higher the levels of protein and Rnas produced by the PHGDH protein, the more advanced the illness.
According to Zhong, that correlation has since been verified in a number of cohorts from various medical centers.
The research team decided to investigate whether there was a causal effect in this most recent study because they were intrigued by this reproducible correlation.
Using mice and human brain organoids, the researchers found that altering the amounts of PHGDH expression had consequential effects on Alzheimer’s disease: lower levels corresponded to less disease progression, whereas increasing the levels led to more disease advancement.
Thus, the researchers discovered that PHGDH is actually the cause of spontaneous Alzheimer’s disease.
The researchers discovered, with the aid of AI, that PHGDH triggers a pathway that disrupts how cells in the brain turn on and off genes, in order to further support that discovery. And such a disturbance can cause issues, like the development of Alzheimer’s disease.
moonlighting position
A neurotransmitter and essential amino acid, serine, is produced by PHGDH by creating an enzyme crucial for its production. Because PHGDH’s enzymatic activity was its only known role, the researchers hypothesized that its metabolic function must be connected to an Alzheimer’s outcome. However, all of their experiments that were intended to demonstrate this failed.  ,
” At that time, our study hit a wall, and we didn’t have a clue of what mechanism it is”, said Zhong.
However, all of this was altered by another Alzheimer’s project he conducted in his lab, which did not concentrate on PHGDH. A year ago, that project revealed a trait that characterizes Alzheimer’s disease: a pervasive imbalance in the brain that affects the way that cells decide which genes are turned on and off in order to perform their specific functions.  ,
The researchers turned to modern AI for assistance because they were curious if PHGDH had an undetermined regulatory role in that process.
They were able to visualize the PHGDH protein’s three-dimensional structure using AI. Within that 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 similarities are only found in the structure and not the protein sequence.
According to Zhong, “it really required contemporary AI to create this discovery very precisely.”
After discovering the substructure, the team then demonstrated that with it, the protein can activate two critical target genes. That disrupts the delicate balance, which causes a number of issues and the onset of Alzheimer’s disease’s early stages.
In other words, PHGDH plays a previously undiscovered, unrelated enzymatic role that is facilitated by a novel pathway that causes Alzheimer’s disease in a first person.  ,
That is in line with the team’s earlier studies: the PHGDH gene produced more proteins in Alzheimer’s patients ‘ brains than the control brains, and these higher levels of the protein in the brain created the imbalance.
Despite the fact that every person has a PHGDH gene, the difference depends on the gene’s level of expression or the number of proteins it produces.
Treatment option
Now that the researchers have identified the mechanism, they wanted to know how to proceed and, in turn, how to put a therapeutic candidate to the study that might help with the disease’s target.  ,
While many current treatments focus on treating the abnormal buildup of the sticky protein called beta-amyloid in the brain, some studies suggest that treating those plaques may be ineffective: essentially by that stage of accumulation, treatment is too late.
However, the crucial pathway identified in this study is upstream, so preventing this pathway can prevent amyloid plaque formation in the first place.
There have been studies on PHGDH’s potential inhibitors because it is such a crucial enzyme. One small molecule, known as NCT-503, stood out to the researchers because it is not quite effective at impeding PHGDH’s enzymatic activity ( the production of serine ), which they did not want to change. NCT-503 has a desirable ability to elude the blood-brain barrier.
They turned to AI once more for three-dimensional modeling and visualization. They found that NCT-503 can access that DNA-binding substructure of PHGDH, thanks to a binding pocket. They discovered that NCT-503 does indeed interfere with PHGDH’s regulatory function with more testing.
When the researchers tested NCT-503 in two mouse models of Alzheimer’s disease, they discovered that it had a significant effect on Alzheimer’s progression. The treated mice demonstrated substantial improvement in their memory and anxiety tests.
These tests were chosen because Alzheimer’s patients have cognitive decline and increased anxiety.
The researchers do acknowledge their study’s limitations. One being that there is no perfect animal model for spontaneous Alzheimer’s disease. Only the mouse models that are available, which have mutations in those known disease-causing genes, could be used to test NCT-503.
The outcomes are still promising, Zhong claims.
” Now there is a therapeutic candidate with demonstrated efficacy that has the potential of being further developed into clinical tests”, said Zhong. ” There may be completely new classes of small molecules that can potentially be used to develop novel treatments.”
He noted that unlike the current treatments that require infusions, small molecules can even be given orally.
The next steps will be to optimize the compound and subject it to FDA IND-enabling studies.
About this research on AI and Alzheimer’s disease
Author: Liezel Labios
Source: UCSD
Contact: Liezel Labios – UCSD
Image: The image is credited to Neuroscience News
Original Research: Open access.
Sheng Zhong et al.,” Transcriptional regulation by PHGDH drives amyloid pathology in Alzheimer’s disease.” Cells
Abstract
Transcriptional regulation by PHGDH drives amyloid pathology in Alzheimer’s disease
Most people over the age of 65 or older have at least one early pathology of Alzheimer’s disease ( AD), but many do not have APOE4 risk alleles, and most do not have disease-causing mutations in APP, PSEN, or MAPT.
This raises questions about the general population’s tolerance for AD. Although transcriptional dysregulation has not traditionally been a hallmark of AD, recent studies reveal significant epigenomic changes in late-onset AD ( LOAD ) patients.
We demonstrate that LOAD biomarker phosphoglycerate dehydrogenase ( PHGDH) expression is independent of its enzymatic activity in mouse and human brain organoids.
PHGDH plays an unidentified role in transcriptional regulation, promoting the transcription of astrocytes ‘ high-mobility group box 1 ( HMGB1 ) and nuclear factor kappa-B kinase subunit alpha ( IKKa ), which inhibit autophagy and exacerbate 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 the role of transcription in LOAD and offer advice for therapeutic approaches that go beyond focusing on familial mutations.
