Amyloid beta modulation of neuronal network activity in vitro

• Published in: Brain research Vol. 1629; pp. 1 - 9
• Main Authors: Charkhkar, Hamid, Meyyappan, Susheela, Matveeva, Evgenia, Moll, Jonathan R, McHail, Daniel G, Peixoto, Nathalia, Cliff, Richard O, Pancrazio, Joseph J
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.12.2015
• Subjects: Action Potentials - drug effects; Action Potentials - physiology; Alzheimer Disease - drug therapy; Alzheimer׳s disease; Amyloid beta; Amyloid beta-Peptides - toxicity; Animals; Cells, Cultured; Drug Evaluation, Preclinical - methods; Female; Functional assay; In vitro models; Memantine - pharmacology; Memantine - therapeutic use; Mice; Microelectrode array; Nerve Net - drug effects; Nerve Net - physiology; Neurology; Neuronal networks; Neurons - drug effects; Neurons - physiology; Peptide Fragments - toxicity; Pregnancy; Receptors, N-Methyl-D-Aspartate - agonists; Receptors, N-Methyl-D-Aspartate - physiology; Alzheimer׳s disease; Microelectrode array; Amyloid beta; In vitro models; Functional assay; Neuronal networks
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2015.09.036

Abstract In vitro assays offer a means of screening potential therapeutics and accelerating the drug development process. Here, we utilized neuronal cultures on planar microelectrode arrays (MEA) as a functional assay to assess the neurotoxicity of amyloid-β 1-42 (Aβ42 ), a biomolecule implicated in the Alzheimer׳s disease (AD). In this approach, neurons harvested from embryonic mice were seeded on the substrate-integrated microelectrode arrays. The cultured neurons form a spontaneously active network, and the spiking activity as a functional endpoint could be detected via the MEA. Aβ42 oligomer, but not monomer, significantly reduced network spike rate. In addition, we demonstrated that the ionotropic glutamate receptors, NMDA and AMPA/kainate, play a role in the effects of Aβ42 on neuronal activity in vitro . To examine the utility of the MEA-based assay for AD drug discovery, we tested two model therapeutics for AD, methylene blue (MB) and memantine. Our results show an almost full recovery in the activity within 24 h after administration of Aβ42 in the cultures pre-treated with either MB or memantine. Our findings suggest that cultured neuronal networks may be a useful platform in screening potential therapeutics for Aβ induced changes in neurological function.