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-APP Swe , and APP23 models. The tg-APP ArcSwe 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. One Sentence Summary Cryo-EM structures of Aβ fibrils extracted from brains of mouse models used for Alzheimer’s disease preclinical research are presented.

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