Death induced by survival gene elimination (DISE) contributes to neurotoxicity in Alzheimer's disease

Alzheimer’s disease (AD) is characterized by progressive neurodegeneration, but the specific events that cause cell death remain poorly understood. Death Induced by Survival gene Elimination (DISE) is a recently discovered powerful cell death mechanism mediated by short (s) RNAs including micro (mi) RNAs acting through the RNA induced silencing complex (RISC). G-rich 6mer seed sequences in the sRNAs (position 2-7) target hundreds of C-rich seed matches in genes essential for cell survival resulting in the simultaneous activation of multiple cell death pathways. Using Argonaute precipitation and RNAseq (Ago-RP-Seq) we analyzed RISC bound sRNAs (R-sRNAs) in in vitro models and in the brains of multiple in vivo AD mouse models, aged mice, and AD patients. In in vitro cell line studies we find evidence for a contribution of RNAi to the toxicity by toxic Aβ42 oligomers. In addition, in AD mouse models with neurodegeneration, and in the aging brain R-sRNAs RISC bound sRNAs show a shift to more toxic seeds. In contrast, in cells that survived in post-mortem brains of AD patients and the brains of “SuperAgers”, individuals over age 80 who have superior memory performance, R-sRNAs shift to more nontoxic seeds, supporting a protective function of miRNAs. Our data provide first evidence of a contribution of DISE to the neurotoxicity seen in AD suggesting that increasing the levels of protective miRNAs in the brain or blocking the activity of toxic R-sRNAs could lead to a novel way of treating the disease. Significance Statement This work explores a contribution of Death Induced by Survival gene Elimination (DISE), a powerful cell death mechanism based on RNA interference (RNAi) to the neurotoxicity seen in Alzheimer’s disease (AD) which has solely been attributed to toxic proteins (e.g., the amyloid precursor protein or phosphorylated Tau). We show a significant association between the occurrence of toxic short (s)RNAs bound to the RNA induced silencing complex (RISC, which mediates RNAi) and the neurotoxicity seen in various AD models and patients. In addition, toxic oligomeric fragments of APP induce toxicity in part by increasing RISC bound toxic sRNAs and require the RISC component Ago2. Our work offers an alternative view on the cause of the neurotoxicity seen in neurodegenerative diseases.