Abstract
Neurotoxicity and the accumulation of extracellular amyloid-beta1–42 (Aβ) peptides are associated with the development of Alzheimer’s disease (AD) and correlate with neuronal activity and network dysfunctions, ultimately leading to cellular death. However, research on neurodegenerative diseases is hampered by the paucity of reliable readouts and experimental models to study such functional decline from an early onset and to test rescue strategies within networks at cellular resolution. To overcome this important obstacle, we demonstrate a simple yet powerful in vitro AD model based on a rat hippocampal cell culture system that exploits large-scale neuronal recordings from 4096-electrodes on CMOS-chips for electrophysiological quantifications. This model allows us to monitor network activity changes at the cellular level and to uniquely uncover the early activity-dependent deterioration induced by Aβ-neurotoxicity. We also demonstrate the potential of this in vitro model to test a plausible hypothesis underlying the Aβ-neurotoxicity and to assay potential therapeutic approaches. Specifically, by quantifying N-methyl D-aspartate (NMDA) concentration-dependent effects in comparison with low-concentration allogenic-Aβ, we confirm the role of extrasynaptic-NMDA receptors activation that may contribute to Aβ-neurotoxicity. Finally, we assess the potential rescue of neural stem cells (NSCs) and of two pharmacotherapies, memantine and saffron, for reversing Aβ-neurotoxicity and rescuing network-wide firing.
Highlights
Alzheimer’s disease (AD) is an irreversible, progressive, neurodegenerative brain ailment characterized by memory loss and synaptic dysfunction[1,2,3]
At 24 days in vitro (DIV), control and Aβ-oligomers solutions were added to the cell culture media after recording the baseline activity of each sample with the 4096 electrodes of the CMOS-multielectrode arrays (MEAs)
The Aβ-treated group showed a prominent decrease in the mean firing and bursting activities and in the number of firing neurons (Fig. 2a and Supplementary Fig. S2a,b), while after 26 h, controls maintained their level of activity
Summary
Alzheimer’s disease (AD) is an irreversible, progressive, neurodegenerative brain ailment characterized by memory loss and synaptic dysfunction[1,2,3]. One increasingly common alternative strategy for confronting these challenges is to advance preclinical in vitro methods that possess complementary in vivo counterparts This strategy enables us to probe-under early conditions of neurotoxicity onset the effects of insults associated with network functions, to pinpoint therapeutic targets, and to advance in testing potential neuroprotective agents prior to long and expensive clinical trials[13]. Among the different techniques for measuring bioelectrical activity in cellular networks, conventional extracellular in vitro recording methods, such as multielectrode arrays (MEAs), provide multisite, label-free, non-invasive and long-term monitoring of spontaneous spiking activity in neuronal cultures; they enable both the detection of the induced toxicity responses of neuronal networks and characterization of the effect of potential therapeutics[16,17,18,19,20]. Functional optical imaging such as Ca2+ imaging can perform multiple single-cell activity mapping but is typically limited by the low temporal resolution and by the difficulty in conducting chronic ongoing recordings over several days[22]
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