Scientists discover Alzheimer’s trigger in the enzyme PHGDH, even without genetic risk

Scientists discover PHGDH enzyme drives Alzheimer’s disease through unexpected gene regulation mechanisms

Scientists have discovered the important mechanism behind Alzheimer’s disease, which provides promising new treatment directions for millions of treatment affected by devastating diseases. The culprit? An enzyme called PHGDH plays a previously unknown role in brain cells.

Researchers at the University of California, San Diego found that elevated levels of phosphoglycerate dehydrogenase (PHGDH) in brain cells called astrocytes can trigger amyloid pathology—even if the accumulation of iconic proteins associated with Alzheimer’s disease, even if no genetic risk factors are associated with the disease.

This finding helps explain the development of Alzheimer’s in people without known genetic mutations or risk factors, addressing key questions in dementia research: Why do so many older people develop the disease?

Major findings of PHGDH in Alzheimer’s disease research

• PHGDH levels are related to disease severity and cognitive impairment in patients with Alzheimer’s disease
• This enzyme promotes the pathology of Alzheimer’s disease through gene regulation, rather than its known enzymatic function
• PHGDH activates inflammatory pathways and damages the natural cleaning process of the brain
• Small molecule inhibitors targeting PHGDH improve memory and reduction of amyloid plaque in mice
• This mechanism operates independently of genetic risk factors such as APOE4

“Almost all people aged 65 or older develop at least the early pathology of Alzheimer’s disease, but most people lack mutations that cause the disease,” the researchers noted in a paper published in their cell. “This raises questions about the development of advertising in the general population.”

Novel mechanisms for the development of Alzheimer’s disease

What makes this discovery striking is how PHGDH causes damage. Instead of completing its known enzymatic activity through its known enzymatic activity, PHGDH completely switches its role, a gene regulator that promotes inflammation and damages autophagy, a natural cleaning process for the brain.

The team demonstrated this by introducing mutations that eliminate PHGDH enzymatic function but keep its regulatory capacity intact. The mutated enzyme still promotes amyloid accumulation, confirming that this previously uncharacterized effect is the cause of the disease process.

“PHGDH has an uncharacterized role in transcriptional regulation,” the researchers explained, how enzymes affect the activity of other genes involved in inflammation and cell cleanup.

Can the goal of this transcription function provide a new approach to treating the failure of other methods?

Multiple experimental models support discovery

The researchers used several complementary methods to verify their findings. Amyloid levels increased significantly in mice designed to produce more PHGDH in brain cells. When they reduce PHGDH (miniature lab-grown brain-like tissue) in human brain organs, amyloid aggregates reduce and protect neural connections.

Most notably, the team identified a small molecule called NCT-503 that could disrupt the harmful regulatory activity of PHGDH without affecting its necessary metabolic function. When administered to mice with Alzheimer’s disease pathology, NCT-503 reduced amyloid plaques by about 50% in key brain regions.

Cognitive function in behavioral testing has improved

In a Barnes maze test that evaluates spatial learning and memory, mice treated with NCT-503 showed improved performance compared to untreated mice with similar pathology. The compound also reduces anxiety-like behavior in these animals.

The researchers believe that PHGDH then inhibits autophagy and accelerates amyloid pathology by activating two key regulatory proteins – IKKA and HMGB1 -. When these proteins are reduced simultaneously, the pathology of Alzheimer’s disease improves, confirming the importance of this pathway.

Early detection potential

PHGDH enzyme has been previously identified as a biomarker of Alzheimer’s disease, and even before clinical symptoms appear, the increased levels observed in the patient’s brain tissue and plasma. This study establishes the role of its causal relationship in disease development, potentially facilitating early intervention.

Although these findings can be translated into human treatment, this study provides a compelling explanation for how Alzheimer’s disease develops in the general population and determines promising intervention goals.

As our population age and cases of Alzheimer’s continue to rise, understanding these fundamental disease mechanisms and targeting them in innovative ways may be critical to developing effective therapies for millions of devastating diseases around the world.