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 <i>MEG3</i> was strongly up-regulated in human neurons<i>.</i> This neuron-specific long noncoding RNA is also up-regulated in AD patients. <i>MEG3</i> expression alone was sufficient to induce necroptosis in human neurons in vitro. Down-regulation of <i>MEG3</i> 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.