The R and Sstructures were analyzed previously using a broad range of biophysical techniques including X-ray diffraction, CD, hydrogendeuterium exchange Raman spectroscopy, FTIR spectroscopy, hydrogen-deuterium exchange monitored by FTIR, proteinase K -digestion assay, binding of a conformation-sensitive fluorescence dye, immunoconformational assay, atomic force microscopy and electron microscopy. The R- and S-KN 93 fibrils were found to have fundamentally different secondary, tertiary and quaternary structures. While both amyloid states displayed a meridional X-ray JNJ 47965567 diffraction typical for amyloid cross-b spines, they showed markedly different equatorial profiles suggesting fundamentally different architectures of the cross b-spine. Using solid state NMR, the cross-b core of R-fibrils was found to consist of in-register, parallel b-sheet structure. No molecular details are currently available from NMR methods about structure of S-fibrils. Nevertheless, together with previous studies this work demonstrates that the relationship between fibril size and their cytotoxic potential is not unidirectional and is controlled by the molecular structures of the amyloid states. The current work demonstrated the remarkable ability of cells to recognize and respond differently to conformationally distinct amyloid states even if they are formed within the same amino acid sequence. As evident from previous studies, not only were the cross b-spine structures markedly different in R- and S-fibrils, but also their surface epitope presentation and PK-resistant regions. For instance, the epitope to R1 antibodies was found to be solvent exposed in S-fibrils, but buried in the fibrillar interior in R-structures. The N-terminal region 23�C,50 was found to be PK-resistant in S-structures, but PK-sensitive in R-fibrils. As judged from the epitope presentation and PKresistant profile, R-fibrils resembled the structure of PrPSc more closely than the S-fibrils. Moreover, unlike S-fibrils, R-fibrils were found to be capable of inducing a transmissible form of prion diseases in wild type animals. Unexpectedly, fragmentation of R-amyloids into fibrils of shorter length was found to abolish their cytotoxic potential, an observation that contradicts the currently dominating view. We do not know whether the cellular response is controlled by S-specific differences in their cross b-spines or by differences in the presentation of epitopes on lateral fibrillar surfaces.