Tau aggregates disrupt heterochromatin condensation by displacing HP1α from H3K9me3-modified chromatin, leading to transposable element reactivation that generates Z-RNA death ligands which activate ZBP1-dependent neuronal necroptosis, and genetic inhibition of ZBP1 provides superior long-term neuroprotection compared to downstream necroptosis effectors in tau-mediated neurodegeneration.

Although the causes of Tau aggregates vary, once Tau aggregates are formed, their neurotoxicity significantly contributes to neuronal death and cognitive decline in tauopathies, with Alzheimer’s disease (AD) being the most well-known example. Despite its central pathogenic role, however, effective therapeutic strategies targeting neurotoxicity of Tau remain poor. Here we demonstrate the pathogenic role of neuronal cell death in Tau-related neurodegeneration. Tau-expressing neurons undergo cell death through Z-DNA-binding protein 1 (ZBP1) activation triggered by endogenous Z-RNAs. These Z-RNAs are derived from reactivated transposable elements (TEs) that are typically silenced within heterochromatin. Tau aggregates show a strong affinity for H3K9me3-modified chromatin, effectively sequestering these epigenetic marks from Heterochromatin Protein 1 (HP1), thereby disrupting the condensation of constitutive heterochromatin. Clinically, an inverse correlation between ZBP1 expression levels in excitatory neurons and cognitive performance in AD patients was observed. Importantly, Zbp1 haploinsufficiency significantly ameliorated cognitive deficits in aged Tau-transgenic mice (24-month-old), highlighting the therapeutic potential of ZBP1 inhibition to strive against neurodegeneration in tauopathies.