Metabolic Reprogramming Rejuvenates Aged Myeloid Cells Restoring Cognition

Area of Science:

• Neuroscience
• Immunology
• Metabolism

Background:

• Aging-associated cognitive loss and neurodegeneration are linked to inflammaging.
• Nonsteroidal anti-inflammatory drugs (NSAIDs) show potential against Alzheimer's disease (AD) by reducing inflammation, but clinical trials have yielded disappointing results.
• Prostaglandin E2 (PGE2), downstream of COX-2, activates EP2 receptors, exacerbating aging-related metabolic dysfunction and inflammation.

Purpose of the Study:

• To investigate the role of EP2 receptors in aging-associated cognitive decline.
• To explore EP2 inhibition as a therapeutic strategy for age-related cognitive impairment and neurodegeneration.

Main Methods:

• Utilized small molecule drugs to inhibit EP2 receptors.
• Assessed changes in myeloid cell polarization, cellular metabolism, mitochondrial morphology, and hippocampus-based memory function in aged models.

Main Results:

• Inhibiting EP2 receptors shifted myeloid cells to an anti-inflammatory phenotype.
• Restored youthful metabolism, improved mitochondrial morphology, and enhanced hippocampus-dependent memory capabilities.
• EP2 inhibition presents a promising alternative to COX inhibition for therapeutic development.

Conclusions:

• EP2 receptor signaling significantly contributes to aging-related cognitive decline and metabolic dysfunction.
• Targeting EP2 offers a potential therapeutic avenue for mild cognitive impairment and neurodegenerative diseases like dementia.
• EP2 may be a more effective therapeutic target than COX enzymes for age-associated cognitive disorders.