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

Background 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. The RISC of most cells is occupied by miRNAs with nontoxic 6mer seeds, which may protect them from DISE by blocking loading of toxic sRNAs. However, during aging when miRNA expression decreases, toxic sRNAs may enter the RISC more readily leaving cells primed for DISE. Whether DISE contributes to neuronal loss in a neurodegenerative disease such as AD has not been evaluated. Methods Using Ago precipitation and RNAseq (Ago-RP-Seq) combined with SPOROS, a recently developed bioinformatics pipeline to analyze small RNAseq data with respect to 6mer seed toxicity, 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. Results We find that in in vitro cell line studies, in mouse models that show neurodegeneration, and in the aging brain R-sRNAs 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. Conclusion 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. ### Competing Interest Statement The authors have declared no competing interest. * 3’UTR : 3’ untranslated region; Aβ : Amyloid-β; Ab42 : 1-42 Aβ peptide; AD:Ago : Argonaute; Ago-RP-Seq : Ago RNA precipitation combined with small RNAseq;Alzheimer’s disease; ATA : aurintricarboxylic acid; BDNF : neurotrophic factor; CN : cognitive normal; DISE : death induced by survival gene elimination; FAD : familial form of AD; iPSC : Induced pluripotent stem cells; k.o. : knockout; NFT : neurofibrillary tangles; p-tau : phosphorylated tau; RA : retinoid acid; RISC : RNA induced silencing complex; RNAi : RNA interferences; SA : SuperAger; SH : SH-SY5Y cells; sRNA : short RNA; R-sRNA : RISC bound sRNA; siRNA : Small interfering RNA; miRNA : microRNA; TNR : trinucleotide repeat; wt : Wild-type.