ENT-AD: A NOVEL COMPOUND SLOWING ALZHEIMER’S DISEASE PROGRESSION

TP1B (Protein Tyrosine Phosphatase 1B, also called PTP-1B) is a negative regulator enzyme that plays a detrimental, disease-promoting role in Alzheimer’s disease (AD). It contributes to several core pathological processes, and inhibiting it (genetically or pharmacologically) consistently improves outcomes in AD mouse models. ENT-AD inhibits microglial cell PTP1B and leads to increased lifespan and markedly improved functionality in an Alzheimer’s mouse model.

PTP1B inhibition is considered a promising strategy for AD because it simultaneously:

  • Enhances Aβ clearance (via microglia)

  • Protects neurons

  • Reduces inflammation

  • Improves insulin signaling and cognition

Existing inhibitors (e.g., ENT-03 and its predecessor molecule trodusquemine/MSI-1436) have shown benefits in our preclinical models, and PTP1B has long been pursued for diabetes/obesity, so some compounds are already in development pipelines. No major human trials for AD yet, but the recent microglial discovery (2026) has renewed excitement.

Impaired microglial phagocytosis of amyloid-β (Aβ): PTP1B is highly expressed in microglia (the brain’s immune cells). It directly dephosphorylates (inactivates) SYK(spleen tyrosine kinase), a key driver of phagocytic activity. This “brakes” microglia, making them less effective at clearing toxic Aβ plaques.

Microglial focus (2026 PNAS study, Cen et al., Tonks lab): Genetic deletion or pharmacological inhibition of PTP1B in APP/PS1 mice (a standard Aβ-based AD model) reduced Aβ plaque burden, shifted microglia toward a pro-phagocytic/immune-activated state, boosted SYK signaling and metabolism, and significantly improved memory/cognition. This was published February 2026 and positions PTP1B inhibition as a way to “revive” plaque-clearing microglia.

PTP1B Inhibition Improves Alzheimer’s and Metabolic Outcomes (2025  Franklin et al.,) In a mouse model of Alzheimer’s disease with type 2 diabetes comorbidity, inhibition of PTP1B improved motor learning and glucose tolerance while reducing neuroinflammation and amyloid-related pathology, supporting PTP1B as a potential therapeutic target for both metabolic and neurodegenerative disease.