Scientists Discover Alzheimer’s Trigger in Enzyme PHGDH — Even Without Genetic Risk

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

Scientists have uncovered a significant mechanism behind Alzheimer’s disease that offers promising new treatment directions for millions affected by this devastating condition. The culprit? An enzyme called PHGDH that plays a previously unknown role in brain cells.

Researchers at the University of California San Diego discovered that elevated levels of phosphoglycerate dehydrogenase (PHGDH) in brain cells called astrocytes can trigger amyloid pathology – the hallmark protein buildup associated with Alzheimer’s – even without genetic risk factors typically linked to the disease.

This finding helps explain how Alzheimer’s develops in people without known genetic mutations or risk factors, addressing a key question in dementia research: why do so many older adults develop the disease?

Key Findings About PHGDH in Alzheimer’s Research

• PHGDH levels correlate with disease severity and cognitive impairment in Alzheimer’s patients
• The enzyme promotes Alzheimer’s pathology through gene regulation rather than its known enzymatic function
• PHGDH activates inflammatory pathways and impairs the brain’s natural cleanup processes
• A small molecule inhibitor targeting PHGDH improved memory and reduced amyloid plaques in mice
• This mechanism operates independently of genetic risk factors like APOE4

“Virtually all individuals aged 65 or older develop at least early pathology of Alzheimer’s disease, yet most lack disease-causing mutations,” the researchers note in their paper published in Cell. “This raises questions about AD development in the general population.”

Novel Mechanism Behind Alzheimer’s Development

What makes this discovery remarkable is how PHGDH causes damage. Rather than working through its known enzymatic activity, PHGDH appears to switch roles entirely, functioning as a gene regulator that promotes inflammation and impairs autophagy – the brain’s natural cleanup process.

The team demonstrated this by introducing mutations that eliminated PHGDH’s enzymatic function but left its regulatory capabilities intact. The mutated enzyme still promoted amyloid buildup, confirming this previously uncharacterized role is what drives the disease process.

“PHGDH has an uncharacterized role in transcriptional regulation,” the researchers explain, describing how the enzyme influences the activity of other genes involved in inflammation and cellular cleanup.

Could targeting this transcriptional function provide a new approach to treating Alzheimer’s where other methods have failed?

Multiple Experimental Models Support Findings

The researchers validated their findings using several complementary approaches. In mice engineered to produce more PHGDH in brain cells, amyloid levels increased significantly. When they reduced PHGDH in human brain organoids – miniature lab-grown brain-like tissues – amyloid aggregates decreased and neural connections were protected.

Most compellingly, the team identified a small molecule called NCT-503 that can disrupt PHGDH’s harmful regulatory activity without affecting its necessary metabolic functions. When administered to mice with Alzheimer’s-like pathology, NCT-503 reduced amyloid plaques by approximately 50% in key brain regions.

Improved Cognitive Function in Behavioral Tests

In the Barnes maze test, which assesses spatial learning and memory, mice treated with NCT-503 demonstrated improved performance compared to untreated mice with Alzheimer’s-like pathology. The compound also reduced anxiety-like behaviors in these animals.

The researchers suggest that PHGDH works by activating two key regulatory proteins – IKKa and HMGB1 – which then suppress autophagy and accelerate amyloid pathology. When these proteins were simultaneously reduced, Alzheimer’s pathology improved, confirming this pathway’s importance.

Early Detection Potential

The PHGDH enzyme had previously been identified as a biomarker for Alzheimer’s, with elevated levels observed in patients’ brain tissue and blood plasma even before clinical symptoms appear. This study establishes its causal role in disease development, potentially enabling earlier intervention.

While substantial work remains before these findings can be translated to human treatments, this research provides a compelling explanation for how Alzheimer’s develops in the general population and identifies a promising target for intervention.

As our population ages and Alzheimer’s cases continue to rise, understanding these fundamental disease mechanisms and targeting them with innovative approaches may prove crucial in developing effective therapies for this devastating condition affecting millions worldwide.