Mechanisms of hyperexcitability in Alzheimer's disease hiPSC-derived neurons and cerebral organoids vs. isogenic control
- The Scripps Research Institute, United States
- Scintillon Institute, United States
Abstract
Human Alzheimer's disease (AD) brains and transgenic AD mouse models manifest hyperexcitability. This aberrant electrical activity is caused by synaptic dysfunction that represents the major pathophysiological correlate of cognitive decline. However, the underlying mechanism for this excessive excitability remains incompletely understood. To investigate the basis for the hyperactivity, we performed electrophysiological and immunofluorescence studies on hiPSC-derived cerebrocortical neuronal cultures and cerebral organoids bearing AD-related mutations in presenilin 1 or amyloid precursor protein vs. isogenic gene corrected controls. In the AD hiPSC-derived neurons/organoids, we found increased excitatory bursting activity, which could be explained in part by a decrease in neurite length. AD hiPSC-derived neurons also displayed increased sodium current density and increased excitatory and decreased inhibitory synaptic activity. Our findings establish hiPSC-derived AD neuronal cultures and organoids as a relevant model of early AD pathophysiology and provide mechanistic insight into the observed hyperexcitability.
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All data generated or analyzed during this study are included in the manuscript and supporting files.
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Funding
National Institutes of Health (P01 HD29587)
- Stuart A Lipton
National Institute of Neurological Disorders and Stroke (Core grant P30 NS076411)
- Stuart A Lipton
National Institutes of Health (DP1 DA041722)
- Stuart A Lipton
National Institutes of Health (R01 NS086890)
- Stuart A Lipton
National Institutes of Health (R01 AG056259)
- Stuart A Lipton
National Institutes of Health (RF1 AG057409)
- Stuart A Lipton
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, Ghatak et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Mechanisms of hyperexcitability in Alzheimer's disease hiPSC-derived neurons and cerebral organoids vs. isogenic control
eLife 8:e50333.
https://doi.org/10.7554/eLife.50333
