<i>In vitro</i> pathological model of Alzheimer's disease based on neuronal network chip and its real-time dynamic analysis_Journal of Biomedical Engineering

Authors：

GAO Fan ¹ , GAO Keqiang ¹ , HE Chuanjiang ¹ , LIU Mengxue ¹ , HU Yanjie ² , YING Kejing ² , WAN Hao ¹ ,  WANG Ping ¹

1. Biosensor National Special Laboratory, Key Laboratory for Biomedical Engineering of Education Ministry, Zhejiang University, Hangzhou 310027, P.R.China;
2. Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310027, P.R.China;

Corresponding author：

WANG Ping, Email: cnpwang@zju.edu.cn

Keywords：

neuronal network chip; Alzheimer’s disease; hippocampal neuron; microelectrode array

DOI：

10.7507/1001-5515.201902014

Video：

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Abstract Full text Figures/Tables Video References Cited by

Alzheimer’s disease (AD) is a chronic central neurodegenerative disease. The pathological features of AD are the extracellular deposition of senile plaques formed by amyloid-β oligomers (AβOs) and the intracellular accumulation of neurofibrillary tangles formed by hyperphosphorylated tau protein. In this paper, an in vitro pathological model of AD based on neuronal network chip and its real-time dynamic analysis were presented. The hippocampal neuronal network was cultured on the microelectrode array (MEA) chip and induced by AβOs as an AD model in vitro to simultaneously record two firing patterns from the interneurons and pyramidal neurons. The spatial firing patterns mapping and cross-correlation between channels were performed to validate the degeneration of neuronal network connectivity. This biosensor enabled the detection of the AβOs toxicity responses, and the identification of connectivity and interactions between neuronal networks, which can be a novel technique in the research of AD pathological model in vitro.

Citation： GAO Fan, GAO Keqiang, HE Chuanjiang, LIU Mengxue, HU Yanjie, YING Kejing, WAN Hao, WANG Ping. In vitro pathological model of Alzheimer's disease based on neuronal network chip and its real-time dynamic analysis. Journal of Biomedical Engineering, 2019, 36(6): 893-901. doi: 10.7507/1001-5515.201902014 Copy

1.	Hyman B T, Phelps C H, Beach T G, et al. National institute on aging-Alzheimer's association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimers Dement, 2012, 8(1): 1-13.
2.	Sosa L J, Cáceres A, Dupraz S, et al. The physiological role of the amyloid precursor protein as an adhesion molecule in the developing nervous system. J Neurochem, 2017, 143(1): 11-29.
3.	Sheng M, Sabatini B L, Sudhof T C. Synapses and Alzheimer's disease. Cold Spring Harb Perspect Biol, 2012, 4(5): 747-749.
4.	Gan K J, Silverman M A. Dendritic and axonal mechanisms of Ca²⁺ elevation impair BDNF transport in Aβ oligomer-treated hippocampal neurons. Mol Biol Cell, 2015, 26(6): 1058-1071.
5.	Scheefhals N, Macgillavry H D. Functional organization of postsynaptic glutamate receptors. Mol Cell Neurosci, 2018, 91: 82-94.
6.	Decker H, Lo K Y, Unger S M, et al. Amyloid-beta peptide oligomers disrupt axonal transport through an NMDA receptor-dependent mechanism that is mediated by glycogen synthase kinase 3β in primary cultured hippocampal neurons. J Neurosci, 2010, 30(27): 9166-9171.
7.	Tu Shichun, Okamoto S I, Lipton S A, et al. Oligomeric Aβ-induced synaptic dysfunction in Alzheimer's disease. Mol Neurodegener, 2014, 9(1): 48.
8.	Bomfim T R, Forny-Germano L, Sathler L B, et al. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease-associated Aβ oligomers. Journal of Clinical Investigation, 2012, 122(4): 1339-1353.
9.	Morris M, Maeda S, Vossel K, et al. The many faces of tau. Neuron, 2011, 70(3): 410-426.
10.	Stern J L, Lessard D V, Hoeprich G J, et al. Phosphoregulation of Tau modulates inhibition of kinesin-1 motility. Mol Biol Cell, 2017, 28(8): 1079-1087.
11.	Kanaan N M, Morfini G, Pigino G A, et al. Phosphorylation in the amino terminus of tau prevents inhibition of anterograde axonal transport. Neurobiol Aging, 2012, 33(4): e15-826.
12.	Mcinnes J, Wierda K, Snellinx A, et al. Synaptogyrin-3 mediates presynaptic dysfunction induced by Tau. Neuron, 2018, 97(4): 823-835.
13.	Cai Xiang, Kallarackal A J, Kvarta M D, et al. Local potentiation of excitatory synapses by serotonin and its alteration in rodent models of depression. Nat Neurosci, 2013, 16(4): 464-U135.
14.	Lu K T, Gean P W. Endogenous serotonin inhibits epileptiform activity in rat hippocampal CA1 neurons via 5-hydroxytryptamine1A receptor activation. Neuroscience, 1998, 86(3): 729-737.
15.	Johnston A, Mcbain C J, Fisahn A. 5-hydroxytryptamine1A receptor-activation hyperpolarizes pyramidal cells and suppresses hippocampal gamma oscillations via Kir3 channel activation. J Physiol, 2014, 592(19): 4187-4199.
16.	Andermann M L, Kerlin A M, Reid R C. Chronic cellular imaging of mouse visual cortex during operant behavior and passive viewing. Front Cell Neurosci, 2010, 4(1): 3.
17.	Robinette B L, Harrill J A, Mundy W R, et al. In vitro assessment of developmental neurotoxicity: use of microelectrode arrays to measure functional changes in neuronal network ontogeny. Front Neuroeng, 2011, 4(4): 1.
18.	Novellino A, Scelfo B, Palosaari T, et al. Development of micro-electrode array based tests for neurotoxicity: assessment of interlaboratory reproducibility with neuroactive chemicals. Front Neuroeng, 2011, 4: 4.
19.	Maccione A, Gandolfo M, Tedesco M, et al. Experimental investigation on spontaneously active hippocampal cultures recorded by means of high-density MEAs: analysis of the spatial resolution effects. Front Neuroeng, 2010, 3(4): 4.
20.	Charkhkar H, Meyyappan S, Matveeva E, et al. Amyloid beta modulation of neuronal network activity in vitro. Brain Res, 2015, 1629: 1-9.
21.	Amin H, Nieus T, Lonardoni D, et al. High-resolution bioelectrical imaging of Aβ-induced network dysfunction on CMOS-MEAs for neurotoxicity and rescue studies. Sci Rep, 2017, 7(1): 2460.
22.	Barthó P, Hirase H, Monconduit L, et al. Characterization of neocortical principal cells and interneurons by network interactions and extracellular features. J Neurophysiol, 2004, 92(1): 600-608.
23.	Greene J R, Radenahmad N, Wilcock G K, et al. Accumulation of calbindin in cortical pyramidal cells with ageing; a putative protective mechanism which fails in Alzheimer's disease. Neuropathol Appl Neurobiol, 2001, 27(5): 339-342.

1. Hyman B T, Phelps C H, Beach T G, et al. National institute on aging-Alzheimer's association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimers Dement, 2012, 8(1): 1-13.
2. Sosa L J, Cáceres A, Dupraz S, et al. The physiological role of the amyloid precursor protein as an adhesion molecule in the developing nervous system. J Neurochem, 2017, 143(1): 11-29.
3. Sheng M, Sabatini B L, Sudhof T C. Synapses and Alzheimer's disease. Cold Spring Harb Perspect Biol, 2012, 4(5): 747-749.
4. Gan K J, Silverman M A. Dendritic and axonal mechanisms of Ca²⁺ elevation impair BDNF transport in Aβ oligomer-treated hippocampal neurons. Mol Biol Cell, 2015, 26(6): 1058-1071.
5. Scheefhals N, Macgillavry H D. Functional organization of postsynaptic glutamate receptors. Mol Cell Neurosci, 2018, 91: 82-94.
6. Decker H, Lo K Y, Unger S M, et al. Amyloid-beta peptide oligomers disrupt axonal transport through an NMDA receptor-dependent mechanism that is mediated by glycogen synthase kinase 3β in primary cultured hippocampal neurons. J Neurosci, 2010, 30(27): 9166-9171.
7. Tu Shichun, Okamoto S I, Lipton S A, et al. Oligomeric Aβ-induced synaptic dysfunction in Alzheimer's disease. Mol Neurodegener, 2014, 9(1): 48.
8. Bomfim T R, Forny-Germano L, Sathler L B, et al. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease-associated Aβ oligomers. Journal of Clinical Investigation, 2012, 122(4): 1339-1353.
9. Morris M, Maeda S, Vossel K, et al. The many faces of tau. Neuron, 2011, 70(3): 410-426.
10. Stern J L, Lessard D V, Hoeprich G J, et al. Phosphoregulation of Tau modulates inhibition of kinesin-1 motility. Mol Biol Cell, 2017, 28(8): 1079-1087.
11. Kanaan N M, Morfini G, Pigino G A, et al. Phosphorylation in the amino terminus of tau prevents inhibition of anterograde axonal transport. Neurobiol Aging, 2012, 33(4): e15-826.
12. Mcinnes J, Wierda K, Snellinx A, et al. Synaptogyrin-3 mediates presynaptic dysfunction induced by Tau. Neuron, 2018, 97(4): 823-835.
13. Cai Xiang, Kallarackal A J, Kvarta M D, et al. Local potentiation of excitatory synapses by serotonin and its alteration in rodent models of depression. Nat Neurosci, 2013, 16(4): 464-U135.
14. Lu K T, Gean P W. Endogenous serotonin inhibits epileptiform activity in rat hippocampal CA1 neurons via 5-hydroxytryptamine1A receptor activation. Neuroscience, 1998, 86(3): 729-737.
15. Johnston A, Mcbain C J, Fisahn A. 5-hydroxytryptamine1A receptor-activation hyperpolarizes pyramidal cells and suppresses hippocampal gamma oscillations via Kir3 channel activation. J Physiol, 2014, 592(19): 4187-4199.
16. Andermann M L, Kerlin A M, Reid R C. Chronic cellular imaging of mouse visual cortex during operant behavior and passive viewing. Front Cell Neurosci, 2010, 4(1): 3.
17. Robinette B L, Harrill J A, Mundy W R, et al. In vitro assessment of developmental neurotoxicity: use of microelectrode arrays to measure functional changes in neuronal network ontogeny. Front Neuroeng, 2011, 4(4): 1.
18. Novellino A, Scelfo B, Palosaari T, et al. Development of micro-electrode array based tests for neurotoxicity: assessment of interlaboratory reproducibility with neuroactive chemicals. Front Neuroeng, 2011, 4: 4.
19. Maccione A, Gandolfo M, Tedesco M, et al. Experimental investigation on spontaneously active hippocampal cultures recorded by means of high-density MEAs: analysis of the spatial resolution effects. Front Neuroeng, 2010, 3(4): 4.
20. Charkhkar H, Meyyappan S, Matveeva E, et al. Amyloid beta modulation of neuronal network activity in vitro. Brain Res, 2015, 1629: 1-9.
21. Amin H, Nieus T, Lonardoni D, et al. High-resolution bioelectrical imaging of Aβ-induced network dysfunction on CMOS-MEAs for neurotoxicity and rescue studies. Sci Rep, 2017, 7(1): 2460.
22. Barthó P, Hirase H, Monconduit L, et al. Characterization of neocortical principal cells and interneurons by network interactions and extracellular features. J Neurophysiol, 2004, 92(1): 600-608.
23. Greene J R, Radenahmad N, Wilcock G K, et al. Accumulation of calbindin in cortical pyramidal cells with ageing; a putative protective mechanism which fails in Alzheimer's disease. Neuropathol Appl Neurobiol, 2001, 27(5): 339-342.

Journal of Biomedical Engineering

In vitro pathological model of Alzheimer's disease based on neuronal network chip and its real-time dynamic analysis

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