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Recent research has revealed that a gene identified as a biomarker for Alzheimer’s disease may actually contribute directly to the illness, unveiling a previously unknown secondary function. A team from the University of California San Diego utilized artificial intelligence to investigate this aspect of Alzheimer’s and to identify a possible treatment that disrupts the gene’s multifaceted role.
The findings were published on April 23 in the journal Cell.
Approximately one in nine individuals aged 65 and older suffers from Alzheimer’s disease, which is the leading cause of dementia. While specific gene mutations can lead to Alzheimer’s, they represent only a small fraction of cases. The majority of patients experience what’s termed “spontaneous” Alzheimer’s, with unclear origins.
Identifying the causes of this spontaneous form could significantly enhance medical interventions.
“Currently, treatment options for Alzheimer’s disease are quite limited, and their effectiveness is not particularly remarkable,” stated senior study author Sheng Zhong, a professor in the Shu Chien-Gene Lay Department of Bioengineering at the UC San Diego Jacobs School of Engineering.
The researchers focused on phosphoglycerate dehydrogenase (PHGDH), which had been previously identified as a potential blood biomarker for early Alzheimer’s detection. A subsequent study established that increased expression levels of the PHGDH gene correlated with the severity of brain changes associated with Alzheimer’s; as production of the PHGDH protein and RNA increased, disease progression followed suit. This relationship has been confirmed across multiple cohorts from various medical institutions, according to Zhong.
Intrigued by this consistent correlation, the research team aimed to ascertain whether PHGDH had a causal relationship with Alzheimer’s in this latest study. By using both mouse models and human brain organoids, they discovered that manipulating PHGDH expression levels had significant impacts on disease progression—lower levels slowed advancement, while higher levels accelerated it. This established PHGDH as a causal gene in spontaneous Alzheimer’s disease.
Further supporting this conclusion, the researchers leveraged AI to identify a new role for PHGDH: it activates a pathway that disrupts gene regulation in brain cells. This disruption can lead to neurological issues, including the development of Alzheimer’s disease.
Moonlighting role
PHGDH produces an enzyme essential for synthesizing serine, an important amino acid and neurotransmitter. Initially, researchers focused solely on PHGDH’s enzymatic activity, believing it to hold the key to understanding its connection to Alzheimer’s. However, all experiments intended to affirm this link were unsuccessful.
“At that point, we felt we had reached an impasse without understanding the mechanism,” Zhong recounted.
A year ago, another Alzheimer’s-focused project within Zhong’s lab uncovered a significant imbalance in brain gene regulation associated with the disease, sparking curiosity about whether PHGDH influenced this process.
Turning to modern AI, researchers visualized the three-dimensional structure of the PHGDH protein, revealing a substructure resembling a known DNA-binding domain found in a category of transcription factors. Notably, this similarity pertained to the structure alone, rather than the protein’s sequence.
Zhong remarked, “It required sophisticated AI methodologies to accurately map out the three-dimensional structure and make this discovery.”
This structural revelation led the team to demonstrate that PHGDH could activate two vital target genes. Such activation disrupts the intricate gene regulatory balance, contributing to the early manifestations of Alzheimer’s disease. Essentially, PHGDH has an undisclosed function that, independent of its metabolic duties, contributes to the onset of spontaneous Alzheimer’s.
This discovery aligns with the team’s previous observations: Alzheimer’s patients exhibited elevated levels of PHGDH proteins in their brains compared to control subjects, with these elevated levels triggering regulatory imbalances. The critical factor is not merely the presence of the PHGDH gene but the expression rate that determines how many proteins it produces.
Treatment option
With the underlying mechanism identified, the researchers set out to explore intervention methods, aiming to discover a therapeutic candidate that could target the disease.
While many existing treatments focus on addressing the accumulation of the toxic protein beta-amyloid in the brain, some studies indicate that once these plaques form, treatment may be too late. In contrast, the newly discovered critical pathway is upstream, suggesting that inhibiting this pathway could prevent amyloid plaque development from the outset.
Given the significance of PHGDH, past research had already looked into potential inhibitors. Among these, one small molecule, NCT-503, piqued the researchers’ interest due to its inability to effectively hinder PHGDH’s enzymatic activity—the production of serine—while still being capable of crossing the blood-brain barrier, an essential quality for any treatment.
Utilizing AI again for three-dimensional modeling, the researchers found that NCT-503 could reach the DNA-binding substructure of PHGDH due to a favorable binding pocket. Subsequent tests confirmed that NCT-503 successfully inhibited PHGDH’s regulatory functions.
When trialed in two mouse models of Alzheimer’s disease, NCT-503 significantly reduced disease progression, leading to marked improvements in memory and anxiety-related tests. These assessments are particularly relevant, as cognitive decline and anxiety are common challenges for Alzheimer’s patients.
Nonetheless, the researchers recognized limitations within their study. One key constraint is the absence of a perfect animal model for spontaneous Alzheimer’s; thus, NCT-503 could only be tested in available mouse models with known genetic mutations linked to the disease.
Despite these limitations, the results are encouraging, according to Zhong.
“We now have a therapeutic candidate with demonstrated efficacy that can be further developed for clinical testing,” said Zhong. “There may even be entirely new classes of small molecules that can be harnessed for future therapeutic innovations.”
The potential benefit of small molecules lies in their versatility, allowing for oral administration, unlike many current treatments that necessitate infusions.
Future steps will involve optimizing this compound and subjecting it to studies necessary for FDA Investigational New Drug (IND) approval.
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