RNA stabilizes soluble seeds from AD brain. Homogenate from AD brain was fractionated in sarkosyl via ultracentrifugation. The supernatant (sup) was further fractionated using SEC. A, resultant fractions were treated with RNase, DNase, or vehicle for 24 h and seeded onto v2L biosensors. The percentage of FRET-positive cells was determined at 48 h. Soluble AD seeds (Sup, >10mer, ∼10mer, trimer, monomer) were highly sensitive to RNase (Sup, >10mer, ∼10mer p < 0.0001, trimer p = 0.0025, monomer p = 0.015, multiple unpaired t tests as compared to control) but not DNase (Sup p = 0.54, >10mer p = 0.68, ∼10mer p = 0.74, trimer p = 0.49, monomer p = 0.45, multiple unpaired t tests as compared to control). Sarkosyl insoluble (SI) AD fibrils were unchanged in all conditions (p = 0.65 RNase versus control, p = 0.28 DNase versus control). Graphs represent data from two experimental replicates, each performed in technical triplicate. These experiments are representative of similar studies performed 12 times overall. Error bars = S.D. B, data from A normalized to untreated control seeding (% FRET positive). AD, Alzheimer’s disease; FRET, fluorescence resonance energy transfer; SEC, size-exclusion chromatography. ∗∗∗∗p < 0.0001, ∗∗∗p < 0.001, ∗∗p < 0.01, ∗p < 0.05.