Increase in Tau Pathology in P290S Mapt Knock-In Mice Crossed with App NL-G-F Mice

• Published in: eNeuro Vol. 9; no. 6; p. ENEURO.0247-22.2022
• Main Authors: Huang, Melissa, Macdonald, Jennifer, Lavenir, Isabelle, Chen, Renren, Craxton, Molly, Slavik-Smith, Elizabeth, Davies, Stephen W., Goedert, Michel
• Format: Journal Article
• Language: English
• Published: United States 01.11.2022
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - pathology; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Animals; Brain - metabolism; Disease Models, Animal; Mice; Mice, Transgenic; Plaque, Amyloid - pathology; tau Proteins - genetics; tau Proteins - metabolism; amyloid-β; tau; Alzheimer’s disease; mouse model; knock-in
• ISSN: 2373-2822; 2373-2822
• DOI: 10.1523/ENEURO.0247-22.2022

Alzheimer’s Disease (AD) is characterized by the pathologic assembly of amyloid β (Aβ) peptide, which deposits into extracellular plaques, and tau, which accumulates in intraneuronal inclusions. To investigate the link between Aβ and tau pathologies, experimental models featuring both pathologies are needed. We developed a mouse model featuring both tau and Aβ pathologies by knocking the P290S mutation into murine Mapt and crossing these Mapt P290S knock-in (KI) mice with the App NL-G-F KI line. Mapt P290S KI mice developed a small number of tau inclusions, which increased with age. The amount of tau pathology was significantly larger in App NL-G-F xMapt P290S KI mice from 18 months of age onward. Tau pathology was higher in limbic areas, including hippocampus, amygdala, and piriform/entorhinal cortex. We also observed AT100-positive and Gallyas-Braak-silver-positive dystrophic neurites containing assembled filamentous tau, as visualized by in situ electron microscopy. Using a cell-based tau seeding assay, we showed that Sarkosyl-insoluble brain extracts from both 18-month-old Mapt P290S KI and App NL-G-F xMapt P290S KI mice were seed competent, with brain extracts from double-KI mice seeding significantly more than those from the Mapt P290S KI mice. Finally, we showed that App NL-G-F xMapt P290S KI mice had neurodegeneration in the piriform cortex from 18 months of age. We suggest that App NL-G-F xMapt P290S KI mice provide a good model for studying the interactions of aggregation-prone tau, Aβ, neuritic plaques, neurodegeneration, and aging.