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DOI: 10.1101/2022.09.08.507157

DISE contributes to neurotoxicity in Alzheimer's disease

B.Paudel S.-Y. Jeong C. P. Martinez ...+15 M. E. Peter
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 cell line models and in the brains of two in vivo AD mouse models and aged mice. In cell line studies we find evidence for a contribution of RNAi to the cell death and DNA damage induced by toxic A{beta}42 oligomers. In addition, in AD mouse models and in the aging brain R-sRNAs RISC bound sRNAs show a shift to more toxic seeds. In contrast, in cells of "SuperAgers", individuals over age 80 who have superior memory performance, R-sRNAs are shifted to more nontoxic seeds, supporting a protective function of miRNAs. Cell death induced by A{beta}42 oligomers can be rescued by adding back protective miRNAs. Our data provide first evidence of a contribution of RNAi to the neurotoxicity and DNA damage 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.