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

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgaveArtikelWetenschappelijkpeer review

7 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)1176-1182
Aantal pagina's7
TijdschriftScience
Volume381
Nummer van het tijdschrift6663
DOI's
StatusGepubliceerd - 15 sep. 2023

Vingerafdruk

Duik in de onderzoeksthema's van 'MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer's disease'. Samen vormen ze een unieke vingerafdruk.

Citeer dit