Cultured neuronal networks on microelectrode arrays as a platform for screening potential Alzheimer’s drugs
Microelectrode arrays (MEAs) are described by Shafer (2011) as “groups of extracellular electrodes that are 10-30 microns in diameter and can be utilized in vivo or in vitro. For in vitro uses, an MEA typically contains up to 64 electrodes and can be utilized to measure the activity of cells and tissues that are electrically excitable, such as neurons, slices of nervous system tissue, and cardiac cells or tissue.” These types of excitable cells show all-or-nothing electrical activity called spikes, which can be detected by MEAs.
Neuronal culture on MEAs is an emerging method for the screening of drugs, chemicals, nanoparticles, and biomaterials for potential neurotoxicity and developmental neurotoxicity. Scientists at the US Environmental Protection Agency have found MEAs useful in screening chemicals, including ToxCast compounds, for neurotoxicity (Valdivia et al., 2014; Wallace et al., 2015).
In the publication by Charkhar, et al. (2015), Amyloid beta modulation of neuronal network activity in vitro, embryonic mouse neuronal networks were cultured on MEAs as a platform for screening potential Alzheimer’s disease (AD) therapeutics. The neurons cultured on MEAs formed a spontaneously, bio-electrically active network. By taking the activity rate as a functional endpoint, the authors were able to monitor the response of the cultured neurons to certain biomolecules associated with Alzheimer’s disease.
The literature reviewed by Charkhar, et al. (2015) explains that soluble amyloid-ß peptides are neurotoxic, and have been implicated in Alzheimer’s disease pathology. The amyloid plaques in Alzheimer’s disease are composed of aggregated long fibrillar amyloid beta (Aß) peptides of several sizes. However, most of the damage happens much earlier to the plaque formation, especially by the shorter peptides, the amyloid-ß 1-42 (Aß42) oligomers. These soluble forms of Aß oligomers are the most neurotoxic, and were reported to correlate with clinical symptoms.
In the MEA assay used by Charkhar, et al. (2015), the Aß42 oligomer significantly reduced neuronal network spike rate, while the monomeric form did not. In cultures pre-treated with either of two model therapeutics, methylene blue or memantine, the spike rate showed an almost full recovery within 24 hours after exposure to neurotoxic doses of Aß42 oligomer. The authors conclude that their “findings show the suitability of neuronal cultures on MEAs as functional assays for neurotoxicity assessment and drug screening in AD research.”
NIH’s Accelerating Medicines Partnership, launched in 2014, explains the need for new therapies for Alzheimer’s disease as follows: “The evidence linking Aß plaque accumulation as the cause of AD has resulted in the development of therapies by many biopharmaceutical companies. However, none to date has demonstrated clinical efficacy in patient trials.” This failure of new drugs at the human clinical trial stage suggests the animal models used for preclinical testing may be ineffective for this purpose. While mouse cells were used in the study described here, one of the benefits of MEA technology is its ability to assess human neuronal and stem cell function. Preclinical models that can replicate relevant mechanistic processes in human cells could improve the success rate of drugs reaching clinical trials, and thus reduce time and costs to new therapeutic breakthroughs.
The highly-funded BRAIN Initiative involves a substantial amount of research using invasive animal methods in brain research, further highlighting the importance of the development of non-animal technologies such as MEAs. The use of MEAs to measure the function of human stem cell and adult neurons, including their responses to drugs and chemicals, and even synaptic connectivity and plasticity, has the potential to reduce the use of animals as well as to provide more physiologically- and species-relevant data in brain research.
Charkhkar, H., Meyyappan, S., Matveeva, E., Moll, J.R., McHail, D.G., Peixoto, N., Cliff, R.O., and Pancrazio, J.J. (2015). Amyloid beta modulation of neuronal network activity in vitro. Brain Res. 1629, 1-9. doi: 10.1016/j.brainres.2015.09.036.
Posted: January 8, 2016