Hierarchical Self-Assembly Mechanism of Ladder-Like Orientated Aβ40 Single-Stranded Protofibrils into Multistranded Mature Fibrils

The complex self-assembly processes in three dimensions of Alzheimer's beta-peptide (A beta) amyloid protofibrils into polymorphic mature fibrils, particularly the relative protofibril orientation and packing mechanism, are poorly understood. We report here the identification and quantification of the hierarchical self-assembly details among distinct A beta 40 fibrils, particularly the winding pictures of two, three, and four individual single-stranded protofibrils into two-, three-, and four-stranded mature fibrils, respectively, via cross-sectional analysis of atomic force microscopy (AFM) images. The statistical polymer physics analysis of fibril flexibilities from AFM characterizations as well as molecular dynamics (MD) simulations reveal a ladder-like packing mechanism rather than a closed-packing manner for the interprotofibril association into A beta 40 mature fibrils. Moreover, our MD results show atomic packing polymorphism at the well-packing interfaces even within the same multistranded fibril. This work provides mechanistic insights into the polymorphic transition of single-stranded A beta 40 protofibrils into multistranded mature fibrils at the mesoscopic level, which is useful for a more comprehensive understanding of Alzheimer's beta-peptide amyloidosis.