NitroSynapsin ameliorates hypersynchronous neural network activity in Alzheimer hiPSC models

Area of Science:

• Neuroscience
• Stem Cell Biology
• Pharmacology

Background:

• Human Alzheimer's disease (AD) brains exhibit early-stage hyperexcitability, leading to synapse loss and cognitive decline.
• Current AD therapies are not disease-modifying, and mouse models poorly predict human treatment efficacy.
• Developing human-based models is crucial for effective AD drug discovery and testing.

Purpose of the Study:

• To establish and utilize human induced pluripotent stem cell (hiPSC)-derived neuronal models for studying Alzheimer's disease (AD) pathology.
• To characterize aberrant electrical activity in human neurons with familial AD mutations.
• To test the efficacy of potential therapeutic compounds in a human cellular context.

Main Methods:

• Utilized patch-clamp electrophysiology, calcium imaging, and multielectrode array (MEA) assays.
• Developed 2D cortical neuronal cultures and 3D cerebral organoids from hiPSCs with familial AD mutations and isogenic wild-type controls.
• Administered the NMDAR antagonist NitroSynapsin and memantine to assess their effects on neuronal activity.

Main Results:

• hiPSC-derived AD neuronal cultures and organoids displayed increased spontaneous action potentials, slow oscillatory events, and hypersynchronous network activity.
• The dual-allosteric NMDAR antagonist NitroSynapsin effectively abrogated the observed hyperactivity.
• The FDA-approved drug memantine did not significantly alter the hyperactivity in these models.

Conclusions:

• Human iPSC-based neuronal models accurately recapitulate AD-associated hyperexcitability.
• NitroSynapsin demonstrates potential as a therapeutic agent for rebalancing aberrant neural networks in AD.
• hiPSC models offer a promising platform for screening drugs to treat hyperexcitability and synaptic damage in Alzheimer's disease.