Validation of a functional human AD model with four AD therapeutics utilizing patterned iPSC-derived cortical neurons integrated with microelectrode arrays

TL;DR

This study validates a human Alzheimer’s disease model using brain cell cultures to test four drugs and assess their effects on memory-related functions before significant cell death occurs.

Contribution

A novel functional AD model using patterned iPSC-derived neurons and MEAs to screen therapeutics at pre-MCI stages is developed and validated.

Findings

Aβ42 oligomers significantly reduced LTP maintenance in the model.

Four AD therapeutics reversed Aβ42-induced LTP impairment.

The system is proposed as a platform for preclinical screening of AD and other neurodegenerative therapeutics.

Abstract

Preclinical methods are needed for screening potential Alzheimer’s disease (AD) therapeutics that recapitulate phenotypes found in the Mild Cognitive Impairment (MCI) stage or even before this stage of the disease. This would require a phenotypic system that reproduces cognitive deficits without significant neuronal cell death to mimic the clinical manifestations of AD during these stages. A potential functional parameter to be monitored is long-term potentiation (LTP), which is a correlate of learning and memory, that would be one of the first functions effected by AD onset. Mature human iPSC-derived cortical neurons and primary astrocytes were co-cultured on microelectrode arrays (MEA) where surface chemistry was utilized to create circuit patterns connecting two adjacent electrodes to model LTP function. LTP maintenance was significantly reduced in the presence of Amyloid-Beta 42 (Aβ42) oligomers compared to the controls, however, co-treatment with AD therapeutics (Donepezil, Memantine, Rolipram and Saracatinib) corrected Aβ42 induced LTP impairment. The results presented here illustrate the significance of the system as a validated platform that can be utilized to model and study MCI AD pathology, and potentially for the pre-MCI phase before the occurrence of significant cell death. It also has the potential to become an ideal platform for high content therapeutic screening for other neurodegenerative diseases.

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