APP processing in human pluripotent stem cell-derived neurons is resistant to NSAID-based γ-secretase modulation

Area of Science:

• Neuroscience
• Pharmacology
• Genetics

Background:

• Elevated amyloid-beta 42 (Aβ42) is implicated in Alzheimer's disease (AD) pathogenesis.
• Gamma-secretase modulators (GSMs), including NSAIDs, show promise in preclinical models but have underperformed in human trials.
• Conventional cell models may not accurately predict drug responses in human neurons.

Purpose of the Study:

• To investigate the efficacy of NSAID-based GSMs in human pluripotent stem cell-derived neurons.
• To determine if human neurons exhibit resistance to NSAID-mediated Aβ42 reduction.
• To emphasize the importance of using relevant human cell models for drug validation in AD research.

Main Methods:

• Utilized human pluripotent stem cell-derived neurons from AD patients and healthy donors.
• Administered pharmaceutically relevant concentrations of NSAID-based GSMs.
• Measured Aβ42/Aβ40 ratios to assess GSM efficacy.

Main Results:

• NSAID-based GSMs demonstrated no effect on Aβ42/Aβ40 ratios in human neurons at tested concentrations.
• Efficacy observed in conventional nonneuronal cell models was not replicated in human neurons.
• Human neurons showed resistance to the Aβ42-lowering effects of NSAID-based GSMs.

Conclusions:

• Human neurons are resistant to NSAID-based gamma-secretase modulation.
• The use of non-human and non-neuronal cells for drug validation may lead to inaccurate predictions of therapeutic efficacy.
• Direct validation in human neuronal models is crucial for developing effective Alzheimer's disease treatments.