MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer's disease

Sriram Balusu; Katrien Horré; Nicola Thrupp; Katleen Craessaerts; An Snellinx; Lutgarde Serneels; Dries T'Syen; Iordana Chrysidou; Amaia M Arranz; Annerieke Sierksma; Joel Simrén; Thomas K Karikari; Henrik Zetterberg; Wei-Ting Chen; Dietmar Rudolf Thal; Evgenia Salta; Mark Fiers; Bart De Strooper

doi:10.1126/science.abp9556

MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer's disease

Sriram Balusu, Katrien Horré, Nicola Thrupp, Katleen Craessaerts, An Snellinx, Lutgarde Serneels, Dries T'Syen, Iordana Chrysidou, Amaia M Arranz, Annerieke Sierksma, Joel Simrén, Thomas K Karikari, Henrik Zetterberg, Wei-Ting Chen, Dietmar Rudolf Thal, Evgenia Salta, Mark Fiers, Bart De Strooper

Netherlands Institute for Neuroscience (NIN)

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

6 Citations (Scopus)

Abstract

Neuronal cell loss is a defining feature of Alzheimer's disease (AD), but the underlying mechanisms remain unclear. We xenografted human or mouse neurons into the brain of a mouse model of AD. Only human neurons displayed tangles, Gallyas silver staining, granulovacuolar neurodegeneration (GVD), phosphorylated tau blood biomarkers, and considerable neuronal cell loss. The long noncoding RNA MEG3 was strongly up-regulated in human neurons. This neuron-specific long noncoding RNA is also up-regulated in AD patients. MEG3 expression alone was sufficient to induce necroptosis in human neurons in vitro. Down-regulation of MEG3 and inhibition of necroptosis using pharmacological or genetic manipulation of receptor-interacting protein kinase 1 (RIPK1), RIPK3, or mixed lineage kinase domain-like protein (MLKL) rescued neuronal cell loss in xenografted human neurons. This model suggests potential therapeutic approaches for AD and reveals a human-specific vulnerability to AD.

Original language	English
Pages (from-to)	1176-1182
Number of pages	7
Journal	Science
Volume	381
Issue number	6663
DOIs	https://doi.org/10.1126/science.abp9556
Publication status	Published - 15 Sept 2023

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Balusu, S., Horré, K., Thrupp, N., Craessaerts, K., Snellinx, A., Serneels, L., T'Syen, D., Chrysidou, I., Arranz, A. M., Sierksma, A., Simrén, J., Karikari, T. K., Zetterberg, H., Chen, W-T., Thal, D. R., Salta, E., Fiers, M., & De Strooper, B. (2023). MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer's disease. Science, 381(6663), 1176-1182. https://doi.org/10.1126/science.abp9556

@article{b30b3a4df9e7404eb505ab4850ef81fd,

title = "MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer's disease",

abstract = "Neuronal cell loss is a defining feature of Alzheimer's disease (AD), but the underlying mechanisms remain unclear. We xenografted human or mouse neurons into the brain of a mouse model of AD. Only human neurons displayed tangles, Gallyas silver staining, granulovacuolar neurodegeneration (GVD), phosphorylated tau blood biomarkers, and considerable neuronal cell loss. The long noncoding RNA MEG3 was strongly up-regulated in human neurons. This neuron-specific long noncoding RNA is also up-regulated in AD patients. MEG3 expression alone was sufficient to induce necroptosis in human neurons in vitro. Down-regulation of MEG3 and inhibition of necroptosis using pharmacological or genetic manipulation of receptor-interacting protein kinase 1 (RIPK1), RIPK3, or mixed lineage kinase domain-like protein (MLKL) rescued neuronal cell loss in xenografted human neurons. This model suggests potential therapeutic approaches for AD and reveals a human-specific vulnerability to AD.",

author = "Sriram Balusu and Katrien Horr{\'e} and Nicola Thrupp and Katleen Craessaerts and An Snellinx and Lutgarde Serneels and Dries T'Syen and Iordana Chrysidou and Arranz, {Amaia M} and Annerieke Sierksma and Joel Simr{\'e}n and Karikari, {Thomas K} and Henrik Zetterberg and Wei-Ting Chen and Thal, {Dietmar Rudolf} and Evgenia Salta and Mark Fiers and {De Strooper}, Bart",

year = "2023",

month = sep,

day = "15",

doi = "10.1126/science.abp9556",

language = "English",

volume = "381",

pages = "1176--1182",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science (AAAS)",

number = "6663",

}

Balusu, S, Horré, K, Thrupp, N, Craessaerts, K, Snellinx, A, Serneels, L, T'Syen, D, Chrysidou, I, Arranz, AM, Sierksma, A, Simrén, J, Karikari, TK, Zetterberg, H, Chen, W-T, Thal, DR, Salta, E, Fiers, M & De Strooper, B 2023, 'MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer's disease', Science, vol. 381, no. 6663, pp. 1176-1182. https://doi.org/10.1126/science.abp9556

TY - JOUR

T1 - MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer's disease

AU - Balusu, Sriram

AU - Horré, Katrien

AU - Thrupp, Nicola

AU - Craessaerts, Katleen

AU - Snellinx, An

AU - Serneels, Lutgarde

AU - T'Syen, Dries

AU - Chrysidou, Iordana

AU - Arranz, Amaia M

AU - Sierksma, Annerieke

AU - Simrén, Joel

AU - Karikari, Thomas K

AU - Zetterberg, Henrik

AU - Chen, Wei-Ting

AU - Thal, Dietmar Rudolf

AU - Salta, Evgenia

AU - Fiers, Mark

AU - De Strooper, Bart

PY - 2023/9/15

Y1 - 2023/9/15

N2 - Neuronal cell loss is a defining feature of Alzheimer's disease (AD), but the underlying mechanisms remain unclear. We xenografted human or mouse neurons into the brain of a mouse model of AD. Only human neurons displayed tangles, Gallyas silver staining, granulovacuolar neurodegeneration (GVD), phosphorylated tau blood biomarkers, and considerable neuronal cell loss. The long noncoding RNA MEG3 was strongly up-regulated in human neurons. This neuron-specific long noncoding RNA is also up-regulated in AD patients. MEG3 expression alone was sufficient to induce necroptosis in human neurons in vitro. Down-regulation of MEG3 and inhibition of necroptosis using pharmacological or genetic manipulation of receptor-interacting protein kinase 1 (RIPK1), RIPK3, or mixed lineage kinase domain-like protein (MLKL) rescued neuronal cell loss in xenografted human neurons. This model suggests potential therapeutic approaches for AD and reveals a human-specific vulnerability to AD.

AB - Neuronal cell loss is a defining feature of Alzheimer's disease (AD), but the underlying mechanisms remain unclear. We xenografted human or mouse neurons into the brain of a mouse model of AD. Only human neurons displayed tangles, Gallyas silver staining, granulovacuolar neurodegeneration (GVD), phosphorylated tau blood biomarkers, and considerable neuronal cell loss. The long noncoding RNA MEG3 was strongly up-regulated in human neurons. This neuron-specific long noncoding RNA is also up-regulated in AD patients. MEG3 expression alone was sufficient to induce necroptosis in human neurons in vitro. Down-regulation of MEG3 and inhibition of necroptosis using pharmacological or genetic manipulation of receptor-interacting protein kinase 1 (RIPK1), RIPK3, or mixed lineage kinase domain-like protein (MLKL) rescued neuronal cell loss in xenografted human neurons. This model suggests potential therapeutic approaches for AD and reveals a human-specific vulnerability to AD.

U2 - 10.1126/science.abp9556

DO - 10.1126/science.abp9556

M3 - Article

C2 - 37708272

SN - 0036-8075

VL - 381

SP - 1176

EP - 1182

JO - Science

JF - Science

IS - 6663

ER -

MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer's disease

Abstract

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