Unlocking Alzheimer’s Mysteries: How PHGDH Changes the Game

Alzheimer’s disease remains one of the most challenging neurodegenerative conditions, particularly in its late-onset form (LOAD), which strikes millions without clear genetic risk factors. Recent research spotlights phosphoglycerate dehydrogenase (PHGDH) as a pivotal player in driving amyloid pathology through an unexpected function: gene transcription regulation. This finding could dramatically shift how we approach diagnosis and treatment for Alzheimer’s.

Key Insights: PHGDH as a Disease Catalyst

• Early Biomarker Potential: PHGDH levels—both as protein and RNA—rise before AD symptoms, tightly correlating with disease severity. This makes PHGDH a promising early indicator for Alzheimer’s.
• Beyond Metabolism: Unlike its well-known enzymatic role in serine synthesis, PHGDH in Alzheimer’s acts as a transcriptional regulator, directly modulating gene expression within astrocytes.
• Initiating Pathology Without Genetics: Overexpressing PHGDH in astrocytes sparks amyloid-beta buildup—a core feature of Alzheimer’s—even in the absence of classic genetic mutations or the APOE4 allele. Reducing PHGDH curbs this effect.
• Critical Downstream Targets: PHGDH upregulates IKKα and HMGB1, which suppress autophagy and activate inflammatory pathways, accelerating amyloid deposits and neurodegeneration.
• Therapeutic Advances: A specialized inhibitor (NCT-503) that crosses the blood-brain barrier blocks PHGDH’s transcriptional activity, leading to reduced amyloid formation and cognitive improvements in animal models—without disturbing healthy serine metabolism.

Decoding the Science

Researchers used advanced mouse models and human brain organoids to manipulate PHGDH expression. Their findings included:

• Lowering PHGDH decreased amyloid buildup and protected synapses; increasing it did the opposite.
• Even enzyme-deficient PHGDH still drove amyloid pathology, highlighting its gene-regulatory function.
• PHGDH moves into the astrocyte nucleus, binds DNA via its HHTH domain, and activates IKKα and HMGB1.
• Only by jointly suppressing IKKα and HMGB1 could they halt PHGDH-driven neurodegeneration, underscoring their essential role in this pathway.

Implications for Patients and Research

• Screening and Early Intervention: Detecting PHGDH exRNA in blood plasma before symptoms emerge offers hope for preclinical Alzheimer’s screening.
• New Therapeutic Targets: Focusing on PHGDH’s transcriptional activity or its downstream genes opens pathways for treatments, particularly for those without genetic risk factors.
• Uncovering Distinct Mechanisms: The PHGDH pathway operates independently of APOE4 and tau, revealing a new angle in Alzheimer’s research.
• Broader Biological Significance: The “moonlighting” role of PHGDH in gene regulation may also clarify its involvement in other neurological and oncological conditions.

A New Frontier in Alzheimer’s Understanding

This breakthrough challenges traditional views of Alzheimer’s as primarily a genetically driven or enzymatic disorder. By uncovering PHGDH’s non-enzymatic, transcriptional influence, scientists have identified a novel mechanism underlying late-onset Alzheimer’s—and a promising target for early detection and innovative therapies. The PHGDH–IKKα–HMGB1 axis is now at the forefront of Alzheimer’s research, offering new hope for effective intervention in the aging population.

Source

Adapted from: joshuaberkowitz.us