Structural basis of memory consolidation mediated by Orb2 amyloid.

In Drosophila, the Orb2 protein (top) is a functional amyloid with self-sustaining prion-like properties that follows an amyloidogenic pathway resembling that of pathological amyloids (bottom). During the assembly pathway, Orb2 and pathological amyloids can form A11-reactive toxic oligomers, and Orb2 can be sequestered by pathological amyloids to form hetero-oligomers. However, intrinsic structural features make Orb2 toxic oligomers rare and transient, suggesting that this functional amyloid appears to have been honed by evolution in adopting a self-sustaining amyloid-like state much more efficiently than pathological amyloids in order to avoid cytotoxicity and perform its role in memory consolidation. This function is supported by the amyloid state of Orb2, since its inhibition by an anti-amyloidogenic peptide (QBP1) selectively interferes with the long-term persistence of memory.