Fig. 7: A hypothetical model that connects DISE, DNA damage, AD, and aging.

a The proposed situation in normal or asymptomatic individuals at a young age. The ratio of nontoxic to toxic sRNAs that are bound to the RISC prevents cells from undergoing DISE. b The proposed situation in older and symptomatic AD patients. Dicer expression is reduced with age resulting in a gradual reduction of nontoxic miRNAs in turn causing a shift in RISC-bound sRNAs to lower 6mer seed viability sensitizing cells to DISE and DNA damage. Tau mediates Aβ42 oligomer (AβO)-induced cell death in part through the RISC and DISE. In contrast, DNA damage induced by Aβ42/tau is dependent on RISC activity. RISC, RNA-induced silencing complex; DISE, death induced by survival gene elimination; sRNA; short RNA. Two inhibitors (blue) and their site of action are shown.