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

Science. 2023 Sep 15;381(6663):1176-1182. doi: 10.1126/science.abp9556. Epub 2023 Sep 14.

Authors

Sriram Balusu^{1

2}, Katrien Horré^{1

2}, Nicola Thrupp^{1

2}, Katleen Craessaerts^{1

2}, An Snellinx^{1

2}, Lutgarde Serneels^{1

2}, Dries T'Syen^{1

2}, Iordana Chrysidou^{1

2}, Amaia M Arranz^{3

4}, Annerieke Sierksma^{1

2}, Joel Simrén^{5

6}, Thomas K Karikari^{5

6

7}, Henrik Zetterberg^{5

6

8

9

10}, Wei-Ting Chen^{1

2}, Dietmar Rudolf Thal^{11

12}, Evgenia Salta¹³, Mark Fiers^{1

2

9}, Bart De Strooper^{1

2

9}

Affiliations

¹ VIB-KU Leuven Center for Brain and Disease Research, 3000 Leuven, Belgium.
² Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium.
³ Achucarro Basque Center for Neuroscience, 48940 Leioa, Spain.
⁴ Ikerbasque Basque Foundation for Science, 48009 Bilbao, Spain.
⁵ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 431 80 Möndal, Sweden.
⁶ Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, 431 80 Möndal, Sweden.
⁷ Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA.
⁸ Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, London WC1N 3BG, UK.
⁹ UK Dementia Research Institute at UCL, London WC1E 6BT, UK.
¹⁰ Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
¹¹ Laboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium.
¹² Department of Pathology, University Hospital Leuven, 3000 Leuven, Belgium.
¹³ Laboratory of Neurogenesis and Neurodegeneration, Netherlands Institute for Neuroscience, 1105BA Amsterdam, Netherlands.

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.

MeSH terms

Alzheimer Disease* / pathology
Animals
Heterografts
Humans
Mice
Necroptosis* / genetics
Neurons* / pathology
Protein Kinases / genetics
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism
Receptor-Interacting Protein Serine-Threonine Kinases / genetics

Substances

MEG3 non-coding RNA, human
RNA, Long Noncoding
RIPK1 protein, human
RIPK3 protein, human
MLKL protein, human
Protein Kinases
Receptor-Interacting Protein Serine-Threonine Kinases

Abstract

MeSH terms

Substances

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