Recent research, significantly aided by artificial intelligence (AI), has uncovered a previously unknown causal link between the gene PHGDH (phosphoglycerate dehydrogenase) and Alzheimer's disease, leading to the identification of a potential therapeutic compound, NCT-503. This groundbreaking work, primarily conducted by researchers at the University of California San Diego and published in the journal Cell, shifts our understanding of PHGDH from merely a biomarker to a direct contributor to the disease's pathology.
PHGDH's Dual Role and Alzheimer's Causation:The PHGDH gene is present in everyone and produces an enzyme essential for synthesizing serine, an amino acid that also functions as a neurotransmitter. For a long time, this enzymatic activity was its only known function. However, studies revealed that individuals with Alzheimer's disease have higher levels of PHGDH protein in their brains compared to healthy individuals, and these elevated levels correlate with more advanced stages of the disease.
The latest research, using AI for 3D visualization and modeling, has unveiled a "moonlighting" or secondary function of PHGDH. Beyond its role in serine production, PHGDH can act as a transcriptional regulator. This means it can bind to DNA and influence gene expression in brain cells, particularly astrocytes (a type of glial cell that supports neurons). This newly discovered regulatory function, distinct from its enzymatic activity, is what researchers now believe directly contributes to the development of spontaneous Alzheimer's disease.
Specifically, elevated levels of PHGDH, through this regulatory role, disrupt the normal balance of gene activity in brain cells. This disruption can initiate a cascade of events, including the suppression of autophagy (the cellular cleanup process) and the acceleration of amyloid pathology (the buildup of amyloid-beta plaques, a hallmark of Alzheimer's). By influencing downstream genes like IKKa and HMGB1, PHGDH can trigger these detrimental processes. Experiments using mice and human brain organoids confirmed this causal link: increasing PHGDH expression worsened Alzheimer's progression, while lowering it reduced disease advancement.
NCT-503: A Promising Therapeutic Candidate:With this new understanding of PHGDH's causal role, researchers began searching for a way to intervene. The goal was to find a compound that could inhibit PHGDH's harmful regulatory function without significantly affecting its essential enzymatic role in serine production. Again, AI played a crucial part in screening small-molecule libraries.
One such molecule, NCT-503, emerged as a particularly promising candidate. Key advantages of NCT-503 include:
- Selective Inhibition: It primarily targets PHGDH's non-canonical gene regulatory function, largely sparing its vital serine-synthesizing activity.
- Blood-Brain Barrier Permeability: NCT-503 can cross the blood-brain barrier, a critical characteristic for any drug intended to treat neurological disorders. AI-powered 3D modeling revealed that NCT-503 can access a specific binding pocket on the DNA-binding substructure of PHGDH.
When tested in two different mouse models of Alzheimer's disease (specifically, models carrying mutations known to cause familial Alzheimer's), NCT-503 demonstrated significant positive effects:
- Reduced Disease Progression: Treatment with NCT-503 led to a notable slowing of the disease's advancement.
- Improved Cognitive Function: Treated mice showed significant improvements in memory.
- Reduced Anxiety: The mice also exhibited diminished anxiety-like behaviors, a common symptom in Alzheimer's patients.
- Lowered Amyloid Plaque Load: These behavioral improvements correlated with a reduction in amyloid-beta plaques in the brain. Importantly, these benefits were achieved without altering brain serine levels, confirming the targeted action of NCT-503.
Researchers acknowledge that current animal models do not perfectly replicate spontaneous Alzheimer's disease in humans. Therefore, NCT-503 was tested in mouse models with known disease-causing mutations. Despite this limitation, the results are considered highly promising.
The next steps involve optimizing NCT-503 or its analogs to enhance properties like pharmacokinetics. Further preclinical studies, including scale-up chemistry and toxicology assessments, are underway to prepare for a potential Investigational New Drug (IND) application to the FDA. If successful, this could pave the way for clinical trials in humans.
Broader Implications:This discovery offers a new therapeutic avenue that targets an "upstream" event in the Alzheimer's disease process. Many current treatments focus on clearing amyloid plaques after they have formed, which may be too late to prevent significant brain damage. By inhibiting PHGDH's detrimental regulatory activity, NCT-503 could potentially intervene earlier in the disease cascade, possibly preventing or delaying both cognitive and neuropsychiatric symptoms before significant amyloid accumulation occurs.
Furthermore, because this mechanism appears independent of familial Alzheimer's mutations, therapies targeting this pathway might benefit a broader population of patients with late-onset Alzheimer's disease (LOAD). Small-molecule inhibitors like NCT-503 also hold the potential for oral administration, which would be a significant advantage over current treatments that often require intravenous infusions.
This research underscores the power of AI in uncovering complex biological mechanisms and accelerating drug discovery, offering new hope in the fight against Alzheimer's disease.