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

Zielinski, M.; Reyes, F. S. P.; Gremer, L.; Schemmert, S.; Frieg, B.; Willuweit, A.; Donner, L.; Elvers, M.; Nilsson, L. N. G.; Syvänen, S.; Sehlin, D.; Ingelsson, M.; Willbold, D.; Schröder, G. F.

doi:10.1101/2023.03.30.534981

bioRxiv · 10.1101/2023.03.30.534981

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

Zielinski, M.·Reyes, F. S. P.·Gremer, L.·Schemmert, S.·Frieg, B.·Willuweit, A.·Donner, L.·Elvers, M.·Nilsson, L. N. G.·Syvänen, S.·Sehlin, D.·Ingelsson, M.·Willbold, D.·Schröder, G. F.

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Abstract

The development of novel drugs for Alzheimers disease has proven difficult, with a high failure rate in clinical trials. Typically, transgenic mice displaying amyloid-{beta} peptide brain pathology are used to develop therapeutic options and to test their efficacy in preclinical studies. However, the properties of A{beta} in such mice have not been systematically compared to A{beta} from the patient brains. Here, we determined the structures of nine ex vivo A{beta} fibrils from six different mouse models by cryo-EM. We found novel A{beta} 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 A{beta} 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 SummaryCryo-EM structures of A{beta} fibrils extracted from brains of mouse models used for Alzheimers disease preclinical research are presented.

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Zielinski, M., Reyes, F. S. P., Gremer, L., Schemmert, S., Frieg, B., Willuweit, A., Donner, L., Elvers, M., Nilsson, L. N. G., Syvänen, S., Sehlin, D., Ingelsson, M., Willbold, D., Schröder, G. F.. 2023-03-31. Cryo-EM Structures of Amyloid-β Fibrils from Alzheimer's Disease Mouse Models. https://doi.org/10.1101/2023.03.30.534981

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