Mechanisms of Hyperexcitability in Alzheimer's Disease HiPSC-derived Neurons and Cerebral Organoids Vs Isogenic Controls

Overview

Journal Elife

Specialty Biology

Date 2019 Nov 30

PMID 31782729

Citations 101

Authors

Swagata Ghatak

Nima Dolatabadi

Dorit Trudler

Xiaotong Zhang

Yin Wu

Madhav Mohata

Rajesh Ambasudhan

Maria Talantova

Stuart A Lipton

Affiliations

Soon will be listed here.

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.

Citing Articles

Calvo B, Schembri-Wismayer P, Duran-Alonso M Cells. 2025; 14(5).

PMID: 40072076 PMC: 11898746. DOI: 10.3390/cells14050347.

S-Nitrosylation of CRTC1 in Alzheimer's disease impairs CREB-dependent gene expression induced by neuronal activity.

Zhang X, Vlkolinsky R, Wu C, Dolatabadi N, Scott H, Prikhodko O Proc Natl Acad Sci U S A. 2025; 122(9):e2418179122.

PMID: 40014571 PMC: 11892585. DOI: 10.1073/pnas.2418179122.

Two- and Three-Dimensional In Vitro Models of Parkinson's and Alzheimer's Diseases: State-of-the-Art and Applications.

Solana-Manrique C, Sanchez-Perez A, Paricio N, Munoz-Descalzo S Int J Mol Sci. 2025; 26(2).

PMID: 39859333 PMC: 11766061. DOI: 10.3390/ijms26020620.

Adenosine deficiency facilitates CA1 synaptic hyperexcitability in the presymptomatic phase of a knockin mouse model of Alzheimer disease.

Bonzanni M, Braga A, Saito T, Saido T, Tesco G, Haydon P iScience. 2025; 28(1):111616.

PMID: 39850358 PMC: 11754081. DOI: 10.1016/j.isci.2024.111616.

Functional network disruption in cognitively unimpaired autosomal dominant Alzheimer's disease: a magnetoencephalography study.

van Nifterick A, de Haan W, Stam C, Hillebrand A, Scheltens P, Van Kesteren R Brain Commun. 2024; 6(6):fcae423.

PMID: 39713236 PMC: 11660908. DOI: 10.1093/braincomms/fcae423.

References

Paquet D, Kwart D, Chen A, Sproul A, Jacob S, Teo S . Efficient introduction of specific homozygous and heterozygous mutations using CRISPR/Cas9. Nature. 2016; 533(7601):125-9. DOI: 10.1038/nature17664. View

Terry R, Masliah E, Salmon D, Butters N, DeTeresa R, Hill R . Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991; 30(4):572-80. DOI: 10.1002/ana.410300410. View

Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar M, Okamoto S . Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci U S A. 2013; 110(27):E2518-27. PMC: 3704025. DOI: 10.1073/pnas.1306832110. View

Yoon S, Elahi L, Pasca A, Marton R, Gordon A, Revah O . Reliability of human cortical organoid generation. Nat Methods. 2018; 16(1):75-78. PMC: 6677388. DOI: 10.1038/s41592-018-0255-0. View

Ghosal K, Vogt D, Liang M, Shen Y, Lamb B, Pimplikar S . Alzheimer's disease-like pathological features in transgenic mice expressing the APP intracellular domain. Proc Natl Acad Sci U S A. 2009; 106(43):18367-72. PMC: 2762847. DOI: 10.1073/pnas.0907652106. View

Penney J, Ralvenius W, Tsai L . Modeling Alzheimer's disease with iPSC-derived brain cells. Mol Psychiatry. 2019; 25(1):148-167. PMC: 6906186. DOI: 10.1038/s41380-019-0468-3. View

Zott B, Simon M, Hong W, Unger F, Chen-Engerer H, Frosch M . A vicious cycle of β amyloid-dependent neuronal hyperactivation. Science. 2019; 365(6453):559-565. PMC: 6690382. DOI: 10.1126/science.aay0198. View

Palop J, Mucke L . Epilepsy and cognitive impairments in Alzheimer disease. Arch Neurol. 2009; 66(4):435-40. PMC: 2812914. DOI: 10.1001/archneurol.2009.15. View

Carter B, Bean B . Incomplete inactivation and rapid recovery of voltage-dependent sodium channels during high-frequency firing in cerebellar Purkinje neurons. J Neurophysiol. 2010; 105(2):860-71. PMC: 3059179. DOI: 10.1152/jn.01056.2010. View

10.

Deyts C, Clutter M, Herrera S, Jovanovic N, Goddi A, Parent A . Loss of presenilin function is associated with a selective gain of APP function. Elife. 2016; 5. PMC: 4915812. DOI: 10.7554/eLife.15645. View

11.

Siskova Z, Justus D, Kaneko H, Friedrichs D, Henneberg N, Beutel T . Dendritic structural degeneration is functionally linked to cellular hyperexcitability in a mouse model of Alzheimer's disease. Neuron. 2014; 84(5):1023-33. DOI: 10.1016/j.neuron.2014.10.024. View

12.

Kwart D, Gregg A, Scheckel C, Murphy E, Paquet D, Duffield M . A Large Panel of Isogenic APP and PSEN1 Mutant Human iPSC Neurons Reveals Shared Endosomal Abnormalities Mediated by APP β-CTFs, Not Aβ. Neuron. 2019; 104(2):256-270.e5. DOI: 10.1016/j.neuron.2019.07.010. View

13.

Wang X, Zhang X, Zhou T, Li N, Jang C, Xiao Z . Elevated Neuronal Excitability Due to Modulation of the Voltage-Gated Sodium Channel Nav1.6 by Aβ1-42. Front Neurosci. 2016; 10:94. PMC: 4783403. DOI: 10.3389/fnins.2016.00094. View

14.

Choi S, Kim Y, Hebisch M, Sliwinski C, Lee S, DAvanzo C . A three-dimensional human neural cell culture model of Alzheimer's disease. Nature. 2014; 515(7526):274-8. PMC: 4366007. DOI: 10.1038/nature13800. View

15.

Lancaster M, Knoblich J . Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc. 2014; 9(10):2329-40. PMC: 4160653. DOI: 10.1038/nprot.2014.158. View

16.

Ullian E, Sapperstein S, Christopherson K, Barres B . Control of synapse number by glia. Science. 2001; 291(5504):657-61. DOI: 10.1126/science.291.5504.657. View

17.

Ciccone R, Franco C, Piccialli I, Boscia F, Casamassa A, de Rosa V . Amyloid β-Induced Upregulation of Na1.6 Underlies Neuronal Hyperactivity in Tg2576 Alzheimer's Disease Mouse Model. Sci Rep. 2019; 9(1):13592. PMC: 6753212. DOI: 10.1038/s41598-019-50018-1. View

18.

Abramov E, Dolev I, Fogel H, Ciccotosto G, Ruff E, Slutsky I . Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses. Nat Neurosci. 2009; 12(12):1567-76. DOI: 10.1038/nn.2433. View

19.

Gonzalez C, Armijo E, Bravo-Alegria J, Becerra-Calixto A, Mays C, Soto C . Modeling amyloid beta and tau pathology in human cerebral organoids. Mol Psychiatry. 2018; 23(12):2363-2374. PMC: 6594704. DOI: 10.1038/s41380-018-0229-8. View

20.

Kim D, MacKenzie Ingano L, Carey B, Pettingell W, Kovacs D . Presenilin/gamma-secretase-mediated cleavage of the voltage-gated sodium channel beta2-subunit regulates cell adhesion and migration. J Biol Chem. 2005; 280(24):23251-61. DOI: 10.1074/jbc.M412938200. View