Cryo-EM Structures of Amyloid-β Fibrils from Alzheimer’s Disease Mouse Models

Abstract

The development of novel drugs for Alzheimer's disease has proven difficult, with a high failure rate in clinical trials. Typically, transgenic mice displaying amyloid-β peptide brain pathology are used to develop therapeutic options and to test their efficacy in preclinical studies. However, the properties of Aβ in such mice have not been systematically compared to Aβ from the patient brains. Here, we determined the structures of nine ex vivo Aβ fibrils from six different mouse models by cryo-EM. We found novel Aβ fibril structures in the APP/PS1, ARTE10, and tg-SwDI models, whereas the human familial type II fibril fold was found in the ARTE10, tg-APPSwe, and APP23 models. The tg-APPArcSwe mice showed an Aβ fibril whose structure resembles the human sporadic type I fibril. These structural elucidations are key to the selection of adequate mouse models for the development of novel plaque-targeting therapeutics and PET imaging tracers.

Divergent age-dependent conformational rearrangement within Aβ amyloid deposits in APP23, APPPS1, and AppNL-Fmice

“…It is known that Aβ amyloid plaque deposits have different microscopic morphologies when stained by immunohistochemistry and amyloid dyes. Aβ1-40 and Aβ1-42 amyloid fibril structural polymorphism is well documented by high resolution structural techniques of fibrils formed in vitro (31, 32) (33) (34) (35) in purified human (7) (36) and mouse brain (37) (25) derived amyloid fibrils, and in seeding experiments using brain derived fibrils as seeds for recombinant Aβ (38) (39). While the overall architecture is common with in-register parallel β-strands arranged in β-arches that comprise the filament structures; the fold, sequence arrangement of intermolecular interactions, and protofilament packing appear dramatically different in the Aβ fibril polymorphs (40).…”

“…This indicates that the age of the mouse or the age of the plaque cannot exclusively explain the difference in plaque morphology between APP23 and App NL-F mice. Notably, App NL-F and APP23 Aβ-amyloid filaments isolated and imaged by Cryo-EM were reported to have the same main structure polymorph (type II) (7) (25). To understand this discrepancy, it is conceivable that LCO staining reports on higher order assemblies of filaments with the same filament fold, or that Cryo-EM preparation (solubilized with sarkosyl, and centrifugation) and selective particle imaging influences the Cryo-EM results.…”

“…Furthermore, fAD also had one predominant polymorph (type II) according to (7), where LCOs showed a separation, while still highly variable, depending on the type of fAD (17). Interestingly App NL-F and APP23 Aβ-amyloid filaments isolated and imaged by the same Cryo-EM procedure were reported to have the same main structure (type II) (7) (25). We therefore herein compared side by side Aβ-amyloid plaque conformational typing by LCO staining of three mouse models (Table S1, Fig.…”