The molecular fidelity of Aβ pathology in 5xFAD and AppNL-FPsen1P117L mice revealed by cryo-EM.

Animal models, particularly mouse models, are indispensable for understanding the pathogenic mechanisms and developing therapeutic and diagnostic drugs for Alzheimer’s diseases (AD). While most AD mouse models aim to mimic amyloid-β (Aβ) pathology in their brains, previous research has demonstrated that not all models succeed in reproducing Aβ fibril structures observed in the brains of AD patients. In this study, we determined cryo-electron microscopy (cryo-EM) structures of Aβ fibrils extracted from the brains of two AD models, 5xFAD and AppNL−FPsen1P117L. The former represents one of the most widely used transgenic AD models, while the latter is the third-generation knock-in model designed to address the issues arising from App overexpression in conventional models. Our results revealed that fibrils from the 5xFAD mouse exhibit a structure nearly identical to human Type II Aβ fibrils found in AD patients, whereas the AppNL−FPsen1P117L mouse predominantly possesses Type II Aβ fibrils but also contains another Aβ fibril species. A subtle discrepancy in main chain arrangement at the position of Val36 was noted among all reported human and mouse Type II structures, potentially originating from variations in the brain microenvironment between human and mice. In conclusion, our findings validated the replication of Aβ pathology in 5xFAD and AppNL−FPsen1P117L mice and provide additional options for selecting appropriate animal models in studies necessitating molecular-level replication of Aβ structures.