Structural Studies of Alzheimer's beta-Amyloid Fibrils

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Linked publications, trials & patents

Abstract

Progress in FY2023 has been in the following area: (1) AMYLOID-BETA FIBRIL STRUCTURES FROM CRYO-ELECTRON MICROSCOPY: We completed and published the analysis of high-quality cryo-EM images of 42-residue amyloid-beta (Ab42) fibrils obtained by seeding synthetic or recombinant Ab42 with amyloid-enriched extract from human brain tissue. The images show two coexisting polymorphs with distinct molecular structures. "Type A" fibrils have an approximately v-shaped Ab42 conformation (similar to the lower-case Greek letter nu), two cross-beta subunits with 2-fold screw symmetry and a right-handed twist, and extensive sets of both intra- and inter-subunit hydrophobic interactions that apparently stabilize the structure. "Type B" fibrils have an approximately u-shaped Ab42 conformation (similat to the lower-case Greek letter upsilon), two cross-beta subunits with 2-fold screw symmetry and a left-handed twist, and hydrophobic interactions that are exclusively inter-subunit in nature. Residues 12-42 are conformationally ordered in Type A fibrils, while residues 1-42 are conformationally ordered in Type B fibrils. Both of these structures are qualitatively distinct form all previously reported Ab42 fibril polymorph structures, including previously reported in vitro and ex vivo polymorphs. A paper describing this work was published in PNAS. (2) PROPAGATION OF AMYLOID-BETA FIBRIL POLYMORPHS IN TRANSGENIC MOUSE BRAINS: Results of a collaboration with Claudio Soto and Rodrigo Morales of the University of Texas Health Science Center at Houston were published in EMBO Reports. This publication includes solid state NMR data that we acquired approximately two years ago, showing that two different 40-residue amyloid-beta (Ab40) polymorphs, prepared in vitro, can be used to induce amyloid pathology by injection into transgenic mouse brains, and that the molecular structures of the resulting amyloid material are different.